Thomas C Doetschman

Interests

Teaching

Colon Cancer, Connective Tissue Disorders, Mouse Genetic Engineering

Research

Functions of TGFbeta and FGF2 in heart development, human heart disease, connective tissue disorders and colon cancer.

Courses

Scholarly Contributions

Chapters

• Doetschman, T. C. (2016). Mediterranean diet, inflammatory bowel diseases, and colon cancer.. In Mediterranean Diet: Dietary Guidelines and Impact on Health and Disease(pp 181-202). Switzerland: Springer International Publishing.
• Sanford, L., Doetschman, T., & Pinkert, C. (2014). Gene targeting in embryonic stem cells: History and methodology. In Transgenic Animal Technology(pp 141-166). Elsevier.
• Doetschman, T., Sanford, L., J.E.Green, ., & T.Ried, . (2012). Overview of designing genetically engineered mouse (GEM) models. In Genetically Engineered Mice for Cancer Research: design, analysis, pathways, validation and pre-clinical testing(pp 1-16). Springer Science+Business Media.
• Bommireddy, R., Doetschman, T., & Sonia B.Jakowlew, . (2008). Tumor Suppressor Functions of TGFbeta1 in T cells. In Cancer Drug Discovery and Development(pp 353-366). Humana Press.
• Bommireddy, R., Doetschman, T., & Luis Graca, . (2007). Transforming growth factor-beta: From its effect in T cell activation to a role in dominant tolerance. In Progress in Inflammation Research(pp 155-168). Birkhauser Verlag.
• Doetschman, T., & Pinkert, C. (2002). Gene targeting in embryonic stem cells: History and methodology. In Transgenic Animal Technology(pp 128-152). Academic Press.
• Schultz, J., Hoying, J., Sullivan, C., Doetschman, T., & Cuevas, P. (2002). FGF and the cardiovascular system. In Fibroblast Growth Factor in the Cardiovascular System(pp 45-66). Holzapfel Publishers.
• Valancius-Mangel, V., Doetschman, T., Puga, A., & Wallace, K. (1999). Potential uses of transgenic and gene-targeted animals in toxicological research.. In Molecular Biology in Toxicology(pp 27-51). Taylor & Frances.
• Kallapur, S., Shull, M., Doetschman, T., Durum, S., & Muegge, K. (1998). Phenotypes of TGFbeta knockout mice. In Contemporary Immunology(pp 335-368). Humana Press.
• Shull, M., Diebold, R., Eis, M., Boivin, G., Grupp, I., Doetschman, T., & Mockrin, S. (1995). Homologous recombination and growth factors.. In Molecular Genetics and Gene Therapy of Cardiovascular Diseases.(pp 1-25). Marcel Dekker, Inc.
• Doetschman, T., & Pinkert, C. (1994). Gene transfer in Embryonic Stem cells. In Transgenic Animal Technology: A laboratory handbook(pp 115-146). Academic Press.
• Shull, M., Kier, A., Diebold, R., Yin, M., Doetschman, T., & Jacob, C. (1994). The importance of transforming growth factor beta1in immunological homeostasis, as revealed by gene ablation in mice. In Overexpression and knockout of cytokines in transgenic mice(pp 135-159). Academic Press.
• Wieczorek, D. H., Doetschman, T., & Pette, D. (1990). Regulation of tropomyosin in embryonic stem cells. In The Dynamic State of Muscle Fibers(pp 91-101). Walter de Gruyter.
• Doetschman T, ., Gossler, A., Kemler, R., Feichtinger, W., & Kemeter, P. (1987). Blastocyst-derived embryonic stem cells as a model for embryogenesis. In Future Aspects In Human In Vitro Fertilization(pp 187-195). Springer.
• Risau, W., Hallmann, R., Sariola, H., Ekblom, P., Kemler, R., Doetschman, T., Rifkin, D., & Klagsburn, M. (1987). Regulation of embryonic blood vessel development. In Angiogenesis: Mechanism and Pathology(pp 134-138). Cold Spring Harbor Laboratories.
• Eppenberger, H., Doetschman, T., Eppenberger, M., Perriard, J., Studer, D., Wallimann, T., Strehler, E., Pearson, M., & Epstein, H. (1982). The M-protein myomesin in cross-striated muscle cells during myofibrillogenesis. In Muscle Development: Molecular and Cellular Control(pp 429-437). Cold Spring Harbor Laboratories.

Journals/Publications

• Doetschman, T. C. (2020). A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet. Int. J. Mol. Sci., 21(21), 7829.
• Ardila, D. C., Tamimi, E., Doetschman, T., Wagner, W. R., & Vande Geest, J. P. (2019). Modulating smooth muscle cell response by the release of TGFβ2 from tubular scaffolds for vascular tissue engineering. Journal of controlled release : official journal of the Controlled Release Society, 299, 44-52.
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  Tissue engineering has gained considerable attention in the development of small diameter tissue engineered vascular grafts (TEVGs) for treating coronary heart disease. A properly designed acellular and biodegradable TEVG must encourage the infiltration and growth of vascular smooth muscle cells (SMCs). Our group has previously shown that increasing levels of TGFβ2 can differentially modulate SMC migration and proliferation. In this study, tubular electrospun scaffolds loaded with TGFβ2 were fabricated using various ratios of gelatin/polycaprolactone (PCL), resulting in scaffolds with porous nano-woven architecture suitable for tissue ingrowth. Scaffold morphology, degradation rate, TGβ2 release kinetics, and bioactivity were assessed. TGFβ2 was successfully integrated into the electrospun biomaterial that resulted in a differential release profile depending on the gelatin/PCL ratio over the course of 42 days. Higher TGFβ2 elution was obtained in scaffolds with higher gelatin content, which may be related to the biodegradation of gelatin in culture media. The biological activity of the released TGFβ2 was evaluated by its ability to affect SMC proliferation as a function of its concentration. SMCs seeded on TGFβ2-loaded scaffolds also showed higher densities and infiltration after 5 days in culture as compared to scaffolds without TGFβ2. Our results demonstrate that the ratio of synthetic and natural polymers in electrospun blends can be used to tune the release of TGFβ2. This method can be used to intelligently modulate the SMC response in gelatin/PCL scaffolds making the TGFβ2-loaded conduits attractive for cardiovascular tissue engineering applications.
• Donovan, M. G., Selmin, O. I., Doetschman, T. C., & Romagnolo, D. F. (2019). Epigenetic Activation of by Genistein In Vivo and Triple Negative Breast Cancer Cells Linked to Antagonism toward Aryl Hydrocarbon Receptor. Nutrients, 11(11).
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  Triple negative breast cancers (TNBC) are the most aggressive and lethal breast cancers (BC). The aryl hydrocarbon receptor (AHR) is often overexpressed in TNBC, and its activation results in the epigenetic silencing of , which is a necessary factor for the transcriptional activation of estrogen receptor (ER)α. The dietary isoflavone genistein (GEN) modulates CpG methylation in BC cells. The purpose of this study was to investigate the effect of GEN on epigenetic regulation and AHR activity in vivo and TNBC cells. Mice were administered a control or GEN-enriched (4 and 10 ppm) diet from gestation through post-natal day 50. Mammary tissue was analyzed for changes in regulation and AhR activity. TNBC cells with constitutively hypermethylated (HCC38) and MCF7 cells were used. Protein levels and mRNA expression were measured by Western blot and real-time PCR, respectively. promoter occupancy and CpG methylation were analyzed by chromatin immunoprecipitation and methylation-specific PCR, respectively. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. GEN administered in the diet dose-dependently decreased basal methylation and AHR activity in the mammary gland of adult mice. HCC38 cells were found to overexpress constitutively active AHR in parallel with hypermethylation. The treatment of HCC38 cells with GEN upregulated BRCA1 protein levels, which was attributable to decreased CpG methylation and AHR binding at exon 1a. In MCF7 cells, GEN prevented the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-dependent localization of AHR at the gene. These effects were consistent with those elicited by control AHR antagonists galangin (GAL), CH-223191, and α-naphthoflavone. The pre-treatment with GEN sensitized HCC38 cells to the antiproliferative effects of 4-hydroxytamoxifen. We conclude that the dietary compound GEN may be effective for the prevention and reversal of AHR-dependent hypermethylation, and the restoration of ERα-mediated response, thus imparting the sensitivity of TNBC to antiestrogen therapy.
• Romagnolo, D. F., Donovan, M. G., Doetschman, T. C., & Selmin, O. I. (2019). -6 Linoleic Acid Induces Epigenetics Alterations Associated with Colonic Inflammation and Cancer. Nutrients, 11(1).
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  The farnesoid-X-receptor (FXR) protects against inflammation and cancer of the colon through maintenance of intestinal bile acid (BA) homeostasis. Conversely, higher levels of BA and cyclooxygenase-2 (COX-2) are risk factors for inflammation and cancer of the colon. In the United States, -6 linoleic acid (LA) is the most commonly used dietary vegetable fat. Metabolism of -6 fatty acids has been linked to a higher risk of intestinal cancer. The objectives of this study were to investigate in colonic mucosa the effects of a high-fat diet rich in LA (-6HFD) on CpG methylation of and prostaglandin-endoperoxide synthase-2 () genes, and the impact on the expression of tumor suppressor adenomatous polyposis Coli () and proliferative cyclin D1 () genes. Weaned C57BL/6J male mice were fed for 6 weeks either an -6HFD containing 44% energy (44%E) from 22% safflower oil (SO, 76% LA by weight) or a 13% energy (13%E) control diet (Control) from SO (5% by weight). Mice fed the -6HFD had reduced (60%) promoter CpG methylation and increased (~50%) mRNA. The expression of FXR-target ileal bile acid-binding protein (), small heterodimer protein (), and anti-inflammatory peroxisome proliferator-activated-γ1 genes was increased. The -6HFD reduced CpG methylation, increased the expression of , and increased CpG methylation in colonic mucosa. Accordingly, reduced expression of was coupled to accumulation of c-JUN and respectively cofactor and gene targets for the β-catenin/Wnt signaling pathway. Finally, the -6HFD reduced the expression of histone deacetylase-1 while favoring the accumulation of acetylated histone 3. We conclude that an -6HFD epigenetically modifies , leading to the activation of downstream factors that participate in BA homeostasis. However, epigenetic activation of coupled with silencing of and accumulation of C-JUN and may increase the risk of inflammation and cancer of the colon.
• Burt, P. M., Xiao, L., Doetschman, T., & Hurley, M. M. (2019). Ablation of low-molecular-weight FGF2 isoform accelerates murine osteoarthritis while loss of high-molecular-weight FGF2 isoforms offers protection. Journal of cellular physiology.
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  FGF2 is an essential growth factor implicated in osteoarthritis (OA), and deletion of full-length FGF2 (Fgf2 ) leads to murine OA. However, the FGF2 gene encodes both high-molecular-weight (HMW) and low-molecular-weight (LMW) isoforms, and the effects of selectively ablating individual isoforms, as opposed to total FGF2, has not been investigated in the context of OA. We undertook this study to examine whether mice lacking HMW FGF2 (Fgf2 ) or LMW FGF2 (Fgf2 ) develop OA and to further characterize the observed OA phenotype in Fgf2 mice. Fgf2 mice never developed OA, but 6- and 9-month-old Fgf2 and Fgf2 mice displayed signs of OA, including eroded articular cartilage, altered subchondral bone and trabecular architecture, and increased OA marker enzyme levels. Even with mechanical induction of OA, Fgf2 mice were protected against OA, whereas Fgf2 and Fgf2 displayed OA-like changes of the subchondral bone. Before exhibiting OA symptoms, Fgf2 or Fgf2 joints displayed differential expression of genes encoding key regulatory proteins, including interleukin-1β, insulin-like growth factor 1, bone morphogenetic protein 4, hypoxia-inducible factor 1, B-cell lymphoma 2, Bcl2-associated X protein, a disintegrin and metalloproteinase with thrombospondin motifs 5, ETS domain-containing protein, and sex-determining region Y box 9. Moreover, Fgf2 OA cartilage exhibited increased FGF2, FGF23, and FGFR1 expression, whereas Fgf2 cartilage had increased levels of FGFR3, which promotes anabolism in cartilage. These results demonstrate that loss of LMW FGF2 results in catabolic activity in joint cartilage, whereas absence of HMW FGF2 with only the presence of LMW FGF2 offers protection from OA.
• Daniel, S. G., Ball, C. L., Besselsen, D. G., Doetschman, T., & Hurwitz, B. L. (2017). Functional Changes in the Gut Microbiome Contribute to Transforming Growth Factor β-Deficient Colon Cancer. mSystems, 2(5).
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  Colorectal cancer (CRC) is one of the most treatable cancers, with a 5-year survival rate of ~64%, yet over 50,000 deaths occur yearly in the United States. In 15% of cases, deficiency in mismatch repair leads to null mutations in transforming growth factor β (TGF-β) type II receptor, yet genotype alone is not responsible for tumorigenesis. Previous work in mice shows that disruptions in TGF-β signaling combined with cause tumorigenesis, indicating a synergistic effect between genotype and microbial environment. Here, we examine functional shifts in the gut microbiome in CRC using integrated -omics approaches to untangle the role of host genotype, inflammation, and microbial ecology. We profile the gut microbiome of 40 mice with/without deficiency in TGF-β signaling from a (mothers against decapentaplegic homolog-3) knockout and with/without inoculation with . Clear functional differences in the microbiome tied to specific bacterial species emerge from four pathways related to human colon cancer: lipopolysaccharide (LPS) production, polyamine synthesis, butyrate metabolism, and oxidative phosphorylation (OXPHOS). Specifically, an increase in drives LPS production, which is associated with an inflammatory response. We observe a commensurate decrease in butyrate production from bacterium A4, which could promote tumor formation. causes an increase in OXPHOS that may increase DNA-damaging free radicals. Finally, multiple bacterial species increase polyamines that are associated with colon cancer, implicating not just diet but also the microbiome in polyamine levels. These insights into cross talk between the microbiome, host genotype, and inflammation could promote the development of diagnostics and therapies for CRC. Most research on the gut microbiome in colon cancer focuses on taxonomic changes at the genus level using 16S rRNA gene sequencing. Here, we develop a new methodology to integrate DNA and RNA data sets to examine functional shifts at the species level that are important to tumor development. We uncover several metabolic pathways in the microbiome that, when perturbed by host genetics and inoculation, contribute to colon cancer. The work presented here lays a foundation for improved bioinformatics methodologies to closely examine the cross talk between specific organisms and the host, important for the development of diagnostics and pre/probiotic treatment.
• Doetschman, T. C. (2017). Genistein prevents BRCA1 CpG methylation and proliferation in human breast cancer cells with activated aromatic hydrocarbon receptor. Current Developments in Nutrition, 1(12), 1-11.
• Doetschman, T. C., Hurwitz, B. L., Besselsen, D. G., Daniel, S. G., & Ball, C. L. (2017). Functional changes in the gut microbiome contribute to Transforming Growth Factor β-deficient colon cancer. mSystems, 2(5), 1-17.
• Doetschman, T., & Georgieva, T. (2017). Gene Editing With CRISPR/Cas9 RNA-Directed Nuclease. Circulation Research, 120(5), 876-894.
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  Genetic engineering of model organisms and cultured cells has for decades provided important insights into the mechanisms underlying cardiovascular development and disease. In the past few years the development of several nuclease systems has broadened the range of model/cell systems that can be engineered. Of these, the CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9) system has become the favorite for its ease of application. Here we will review this RNA-guided nuclease system for gene editing with respect to its usefulness for cardiovascular studies and with an eye toward potential therapy. Studies on its off-target activity, along with approaches to minimize this activity will be given. The advantages of gene editing versus gene targeting in embryonic stem cells, including the breadth of species and cell types to which it is applicable, will be discussed. We will also cover its use in iPSC for research and possible therapeutic purposes; and we will review its use in muscular dystrophy studies where considerable progress has been made toward dystrophin correction in mice. The CRISPR/Ca9s system is also being used for high-throughput screening of genes, gene regulatory regions, and long noncoding RNAs. In addition, the CRISPR system is being used for nongene-editing purposes such as activation and inhibition of gene expression, as well as for fluorescence tagging of chromosomal regions and individual mRNAs to track their cellular location. Finally, an approach to circumvent the inability of post-mitotic cells to support homologous recombination-based gene editing will be presented. In conclusion, applications of the CRISPR/Cas system are expanding at a breath-taking pace and are revolutionizing approaches to gain a better understanding of human diseases.
• Donovan, M. G., Selmin, O. I., Doetschman, T. C., & Romagnolo, D. F. (2017). Mediterranean Diet: Prevention of Colorectal Cancer. Frontiers in Nutrition, 4, 59-83.
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  Colorectal cancer (CRC) is the third most common cancer diagnosis and the second and third leading cause of cancer mortality in men and women, respectively. However, the majority of CRC cases are the result of sporadic tumorigenesis via the adenoma-carcinoma sequence. This process can take up to 20 years, suggesting an important window of opportunity exists for prevention such as switching toward healthier dietary patterns. The Mediterranean diet (MD) is a dietary pattern associated with various health benefits including protection against cardiovascular disease, diabetes, obesity, and various cancers. In this article, we review publications available in the PubMed database within the last 10 years that report on the impact of a MD eating pattern on prevention of CRC. To assist the reader with interpretation of the results and discussion, we first introduce indexes and scoring systems commonly used to experimentally determine adherence to a MD, followed by a brief introduction of the influence of the MD pattern on inflammatory bowel disease, which predisposes to CRC. Finally, we discuss key biological mechanisms through which specific bioactive food components commonly present in the MD are proposed to prevent or delay the development of CRC. We close with a discussion of future research frontiers in CRC prevention with particular reference to the role of epigenetic mechanisms and microbiome related to the MD eating pattern.
• Romagnolo, D. F., Donovan, M. G., Papoutsis, A. J., Doetschman, T. C., & Selmin, O. I. (2017). Genistein Prevents CpG Methylation and Proliferation in Human Breast Cancer Cells with Activated Aromatic Hydrocarbon Receptor. Current developments in nutrition, 1(6), e000562.
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  Previous studies have suggested a causative role for agonists of the aromatic hydrocarbon receptor (AhR) in the etiology of breast cancer 1, early-onset (BRCA-1)-silenced breast tumors, for which prospects for treatment remain poor. We investigated the regulation of by the soy isoflavone genistein (GEN) in human estrogen receptor α (ERα)-positive Michigan Cancer Foundation-7 (MCF-7) and ERα-negative sporadic University of Arizona Cell Culture-3199 (UACC-3199) breast cancer cells, respectively, with inducible and constitutively active AhR. In MCF-7 cells, we analyzed the dose- and time-dependent effects of GEN and (-)-epigallocatechin-3-gallate (EGCG) control, selected as prototype dietary DNA methyltransferase (DNMT) inhibitors, on BRCA-1 expression after AhR activation with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in TCDD-washout experiments. We compared the effects of GEN and EGCG on cytosine-phosphate-guanine (CpG) methylation and cell proliferation. Controls for DNA methylation and proliferation were changes in expression of DNMT-1, cyclin D1, and p53, respectively. In UACC-3199 cells, we compared the effects of GEN and α-naphthoflavone (αNF; 7,8-benzoflavone), a synthetic flavone and AhR antagonist, on expression and CpG methylation, cyclin D1, and cell growth. Finally, we examined the effects of GEN and αNF on , AhR-inducible cytochrome P450 ()-1A1 () and , and mRNA expression. In MCF-7 cells, GEN exerted dose- and time-dependent preventative effects against TCDD-dependent downregulation of BRCA-1. After TCDD washout, GEN rescued BRCA-1 protein expression while reducing DNMT-1 and cyclin D1. GEN and EGCG reduced CpG methylation and cell proliferation associated with increased p53. In UACC-3199 cells, GEN reduced and estrogen receptor-1 () CpG methylation, cyclin D1, and cell growth while inducing BRCA-1 and . Results suggest preventative effects for GEN and EGCG against CpG methylation and downregulation in ERα-positive breast cancer cells with activated AhR. GEN and flavone antagonists of AhR may be useful for reactivation of and ERα via CpG demethylation in ERα-negative breast cancer cells harboring constitutively active AhR.
• Haskett, D. G., Haskett, D. G., Maestas, D., Maestas, D., Howerton, S., Howerton, S., Smith, T., Smith, T., Ardilia, C., Ardilia, C., Doetschman, T. C., Doetschman, T. C., Utzinger, U., Utzinger, U., McGgrath, D. V., Mcgrath, D. V., McIntyre, J. O., McIntyre, J. O., Vande Geest, J. P., & Vande Geest, J. P. (2016). 2-Photon characterization of optical proteolytic beacons for imaging changes in MMP activity in a mouse model of aneurysm. Microscopy and Microanalysis, 22, 349-360. doi:http://dx.doi.org/10.1017/S1431927616000088
• Haskett, D. G., Maestas, D., Howerton, S. J., Smith, T., Ardila, D. C., Doetschman, T., Utzinger, U., McGrath, D., McIntyre, J. O., & Vande Geest, J. P. (2016). 2-Photon Characterization of Optical Proteolytic Beacons for Imaging Changes in Matrix-Metalloprotease Activity in a Mouse Model of Aneurysm. Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada, 1-12.
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  Abdominal aortic aneurysm is a multifactorial disease that is a leading cause of death in developed countries. Matrix-metalloproteases (MMPs) are part of the disease process, however, assessing their role in disease initiation and progression has been difficult and animal models have become essential. Combining Förster resonance energy transfer (FRET) proteolytic beacons activated in the presence of MMPs with 2-photon microscopy allows for a novel method of evaluating MMP activity within the extracellular matrix (ECM). Single and 2-photon spectra for proteolytic beacons were determined in vitro. Ex vivo experiments using the apolipoprotein E knockout angiotensin II-infused mouse model of aneurysm imaged ECM architecture simultaneously with the MMP-activated FRET beacons. 2-photon spectra of the two-color proteolytic beacons showed peaks for the individual fluorophores that enable imaging of MMP activity through proteolytic cleavage. Ex vivo imaging of the beacons within the ECM revealed both microstructure and MMP activity. 2-photon imaging of the beacons in aneurysmal tissue showed an increase in proteolytic cleavage within the ECM (p
• Samadder, P., Weng, N., Doetschman, T., Heimark, R. L., & Galbraith, D. W. (2016). Flow cytometry and single nucleus sorting for Cre-based analysis of changes in transcriptional states. Cytometry. Part A : the journal of the International Society for Analytical Cytology.
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  The organs of eukaryotic organisms comprise complex interspersions of cell types, whose different molecular activities, and corresponding cellular states, cooperate during development to produce the final, functional organ. Dysfunction of organs in disease, particularly oncogenesis, initiates with changes of state of a minor subset of cells. It therefore is hard to detect early molecular indicators of disease within an overwhelming background of normal cells. Flow cytometry and sorting provides a convenient way to purify minority subpopulations, if a specific fluorophore can be unambiguously and exclusively associated with this subpopulation. We have generated a number of transgenic mouse lines expressing a nuclear-localized version of the Green Fluorescent Protein (GFP), within which the production of a chimeric histone 2B-GFP protein occurs under the control of a constitutively-active, actin-derived promoter, separated by a Floxed-STOP sequence. In the presence of Cre recombinase, within F1 progeny of these mouse lines, excision of the STOP sequence activates transcription which results in the emergence of cells containing green fluorescent nuclei. We describe the characterization of these lines using a combination of microscopic imaging, flow cytometry and sorting, and Reverse-Transcription polymerase chain reaction of transcripts within single sorted nuclei isolated from tissue homogenates. These lines should be particularly useful for analysis of transcriptional changes in oncogenesis. © 2016 International Society for Advancement of Cytometry.
• Selmin, O. I., Fang, C., Lyon, A. M., Doetschman, T. C., Thompson, P. A., Martinez, J. D., Smith, J. W., Lance, P. M., & Romagnolo, D. F. (2016). Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells. The Journal of Nutrition, 146, 236-242.
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  The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention.
• Tamimi, E., Ardila, D. C., Haskett, D. G., Doetschman, T., Slepian, M. J., Kellar, R. S., & Vande Geest, J. P. (2016). Biomechanical Comparison of Glutaraldehyde-Crosslinked Gelatin Fibrinogen Electrospun Scaffolds to Porcine Coronary Arteries. Journal of Biomechanical Engineering, 138(1).
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  Cardiovascular disease (CVD) is the leading cause of death for Americans. As coronary artery bypass graft surgery (CABG) remains a mainstay of therapy for CVD and native vein grafts are limited by issues of supply and lifespan, an effective readily available tissue-engineered vascular graft (TEVG) for use in CABG would provide drastic improvements in patient care. Biomechanical mismatch between vascular grafts and native vasculature has been shown to be the major cause of graft failure, and therefore, there is need for compliance-matched biocompatible TEVGs for clinical implantation. The current study investigates the biaxial mechanical characterization of acellular electrospun glutaraldehyde (GLUT) vapor-crosslinked gelatin/fibrinogen cylindrical constructs, using a custom-made microbiaxial optomechanical device (MOD). Constructs crosslinked for 2, 8, and 24 hrs are compared to mechanically characterized porcine left anterior descending coronary (LADC) artery. The mechanical response data were used for constitutive modeling using a modified Fung strain energy equation. The results showed that constructs crosslinked for 2 and 8 hrs exhibited circumferential and axial tangential moduli (ATM) similar to that of the LADC. Furthermore, the 8-hrs experimental group was the only one to compliance-match the LADC, with compliance values of 0.0006±0.00018 mm Hg-1 and 0.00071±0.00027 mm Hg-1, respectively. The results of this study show the feasibility of meeting mechanical specifications expected of native arteries through manipulating GLUT vapor crosslinking time. The comprehensive mechanical characterization of cylindrical biopolymer constructs in this study is an important first step to successfully develop a biopolymer compliance-matched TEVG.
• Yan, J., Mitra, A., Hu, J., Cutrera, J. J., Xia, X., Doetschman, T., Gagea, M., Mishra, L., & Li, S. (2016). Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells. Journal of Hepatology.
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  Sepsis is an acute systemic inflammatory response to infection associated with high patient mortality (28-40%). We hypothesized that interleukin (IL)-30, a novel cytokine protecting mice against liver injury resulting from inflammation, would generate a protective effect against systemic inflammation and sepsis-induced death.
• Ardila, D., Tamimi, E., Danford, F., Haskett, D., Kellar, R., Doetschman, T., & Vande Geest, J. (2015). TGFbeta2 differentially modulates smooth muscle cell proliferation and migration in electrospun gelatin-fibrinogen constructs. Biomaterials, 37, 164-173.
• Homer-Bouthiette, C., Doetschman, T., Xiao, L., & Hurley, M. (2014). Knockout of nuclear high molecular weight FGF2 isoforms in mice modulates bone and phosphate homeostasis. Journal of Biological Chemistry, 289(52), 36303-36314.
• Nusayr, E., Sadideen, D. T., & Doetschman, T. (2013). FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner. Physiological reports, 1(4).
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  Pathological cardiac hypertrophy and cardiac fibrosis are remodeling events that result in mechanical stiffness and pathophysiological changes of the myocardium. Both humans and animal models display a sexual dimorphism where females are more protected from pathological remodeling. Fibroblast growth factor 2 (FGF2) mediates cardiac hypertrophy, cardiac fibrosis and protection against cardiac injury and is made in high molecular weight and low molecular weight isoforms (Hi FGF2 and Lo FGF2, respectively). Although some light has been shed on isoform-specific functions in cardiac pathophysiology, their roles in pathologic cardiac remodeling have yet to be determined. We tested the hypothesis that Lo FGF2 and Hi FGF2 modulate pathological cardiac remodeling in an isoform-specific manner. Young adult male and female mice between 8-12 weeks of age of mixed background that were deficient in either Hi FGF2 or Lo FGF2 (Hi KO or Lo KO, respectively) were subjected to daily injections of isoproterenol (Iso) for four days after which their hearts were compared to wildtype cohorts. Post-Iso treatment, female Lo KO hearts don't exhibit significant differences in their hypertrophic and fibrotic response, while female Hi KO hearts present with a blunted hypertrophic response. In male animals Lo KO hearts present with an exacerbated fibrotic response and increased -smooth muscle actin protein expression while Hi KO hearts present with a blunted fibrotic response and increased atrial natriuretic factor protein expression Thus, in female hearts Hi FGF2 mediate cardiac hypertrophy while in male hearts Lo FGF2 and Hi FGF2 display an antithetical role in cardiac fibrosis where Lo FGF2 is protective while Hi FGF2 is damaging. In conclusion, cardiac remodeling following catecholamine overactivation is modulated by FGF2 in isoform- and sex-specific manners.
• Nusayr, E., Sadideen, D., & Doetschman, T. (2013). FGF2 modulates cardiac remodeling in an isoform- and sex-specific manner. Physiological Reports, 1(4).
• Doetschman, T., & Azhar, M. (2012). Cardiac-specific inducible and conditional gene targeting in mice. Circulation research, 110(11), 1498-512.
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  Mouse genetic engineering has revolutionized our understanding of the molecular and genetic basis of heart development and disease. This technology involves conditional tissue-specific and temporal transgenic and gene targeting approaches, as well as introduction of polymorphisms into the mouse genome. These approaches are increasingly used to elucidate the genetic pathways underlying tissue homeostasis, physiology, and pathophysiology of adult heart. They have also led to the development of clinically relevant models of human cardiac diseases. Here, we review the technologies and their limitations in general and the cardiovascular research community in particular.
• Doetschman, T., Barnett, J., Runyan, R., Camenisch, T., Heimark, R., Granzier, H., Conway, S., & Azhar, M. (2012). Transforming growth factor beta signaling in adult cardiovascular diseases and repair. Cell and Tissue Research, 347(1), 203-223.
• Doetschman, T., Georgieva, T., Li, H., Reed, T., Grisham, C., Friel, J., Estabrook, M., Gard, C., Sanford, L., & Azhar, M. (2012). Generation of mice with a conditional allele for the transforming growth factor beta3 gene. Genesis, 50(1), 59-66.
• Manning, J., Carpenter, G., Porter, D., House, S., Pietras, D., Doetschman, T., & Schultz, J. J. (2012). Fibroblast growth factor-2-induced cardioprotection against myocardial infarction occurs via the interplay between nitric oxide, protein kinase signaling, and ATP-sensitive potassium channels. Growth Factors, 30(2), 124-139.
• Azhar, M., Brown, K., Gard, C., Chen, H., Rajan, S., Elliott, D., Stevens, M., Camenisch, T., Conway, S., & Doetschman, T. (2011). Transforming growth factor Beta2 is required for valve remodeling during heart development. Developmental Dynamics, 240(9), 2127-2141.
• Conway, S., Doetschman, T., & Azhar, M. (2011). The inter-relationship of periostin, TGF beta, and BMP in heart valve development and valvular heart diseases. Scientific World Journal, 11, 1509-1524.
• Doetschman, T., Sholl, A., Chen, H., Gard, C., Hildeman, D., & Bommireddy, R. (2011). Divergent effects of calcineurin Abeta on regulatory and conventional T-cell homeostasis. Clinical Immunology, 138(3), 321-330.
• Fei, Y., Xiao, L., Doetschman, T., Coffin, D., & Hurley, M. (2011). Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the Wnt signaling pathway. Journal of Biological Chemistry, 286(47), 40575-40583.
• House, S., House, B., Glascock, B., Kimball, T., Nusayr, E., Schultz, J., & Doetschman, T. (2010). Fibroblast Growth Factor 2 Mediates Isoproterenol-induced Cardiac Hypertrophy through Activation of the Extracellular Regulated Kinase. Molecular and Cellular Pharmacology, 2(4), 143-154.
• Liao, S., Bodmer, J., Azhar, M., Newman, G., Coffin, J., Doetschman, T., & Schultz, J. J. (2010). The influence of FGF2 high molecular weight (HMW) isoforms in the development of cardiac ischemia-reperfusion injury. Journal of Molecular and Cellular Cardiology, 48(6), 1245-1254.
• Nakao, S., Maruyama, K., Zandi, S., Melhorn, M., Taher, M., Noda, K., Nusayr, E., Doetschman, T., & Hafezi-Moghadam, A. (2010). Lymphangiogenesis and angiogenesis: concurrence and/or dependence? Studies in inbred mouse strains. FASEB Journal, 24(2), 504-513.
• Xiao, L., Sobue, T., Esliger, A., Kronenberg, M., Coffin, J., Doetschman, T., & Hurley, M. (2010). Disruption of the Fgf2 gene activates the adipogenic and suppresses the osteogenic program in mesenchymal marrow stromal stem cells. Bone, 47(2), 360-370.
• Azhar, M., Runyan, R., Gard, C., Sanford, L., Miller, M., Andringa, A., Pawlowski, S., Rajan, S., & Doetschman, T. (2009). Ligand-specific function of transforming growth factor beta in epithelial-mesenchymal transition in heart development. Developmental Dynamics, 238(2), 431-442.
• Azhar, M., Yin, M., Bommireddy, R., Duffy, J., Yang, J., Pawlowski, S., Boivin, G., Engle, S., Sanford, L., Grisham, C., Singh, R., Babcock, G., & Doetschman, T. (2009). Generation of mice with a conditional allele for transforming growth factor beta 1 gene. Genesis, 47(6), 423-431.
• Azhar, M., Yin, M., Zhou, M., Li, H., Mustafa, M., Nusayr, E., Keenan, J., Chen, H., Pawlosky, S., Gard, C., Grisham, C., Sanford, L., & Doetschman, T. (2009). Gene targeted ablation of high molecular weight fibroblast growth factor-2. Developmental Dynamics, 238(2), 351-357.
• Bommireddy, R., Bueno, O., Martin, J., Ormsby, I., Chen, H., Gard, C., Molkentin, J., Boivin, G., Babcock, G., & Doetschman, T. (2009). Calcineurin deficiency decreases inflammatory lesions in transforming growth factor beta1-deficient mice. Clinical and Experimental Immunology, 158(3), 317-324.
• Doetschman, T. (2009). Influence of genetic background on genetically engineered mouse phenotypes. Methods in Molecular Biology, 530, 423-433.
• Liao, S., Bodmer, J., Pietras, D., Azhar, M., Doetschman, T., & Schultz, J. J. (2009). Biological functions of the low and high molecular weight protein isoforms of fibroblast growth factor-2 in cardiovascular development and disease. Developmental Dynamics, 238(2), 249-264.
• Sabbieti, M., Agas, D., Xiao, L., Marchetti, L., Coffin, J., Doetschman, T., & Hurley, M. (2009). Endogenous FGF-2 is critically important in PTH anabolic effects on bone. Journal of Cell Physiology, 219(1), 143-151.
• Snider, P., Standley, K., Wang, J., Azhar, M., Doetschman, T., & Conway, S. (2009). Origin of cardiac fibroblasts and the role of periostin. Circulation Research, 105(10), 934-947.
• Xiao, L., Liu, P., Li, X., Doetschman, T., Coffin, J., Drissi, H., & Hurley, M. (2009). Exported 18-kDa isoform of fibroblast growth factor-2 is a critical determinant of bone mass in mice. Journal of Biological Chemistry, 284(5), 3170-3182.
• Bommireddy, R., Babcock, G., Singh, R., & Doetschman, T. (2008). TGFbeta1 deficiency does not affect the generation and maintenance of CD4+CD25+FOXP3+ putative Treg cells, but causes their numerical inadequacy and loss of regulatory function. Clinical Immunology, 127(2), 206-213.
• Chen, K., Ohkubo, Y., Shin, D., Doetschman, T., Sanford, L., Li, H., & Vaccarino, F. (2008). Decrease in excitatory neurons, astrocytes and proliferating progenitors in the cerebral cortex of mice lacking exon 3 from the Fgf2 gene. BMC Neuroscience, 9, 94.
• Lee, H., Chen, S., Doetschman, T., Deng, C., D'Agati, V., & Kim, M. (2008). Sevoflurane protects against renal ischemia and reperfusion injury in mice via the transforming growth factor-beta1 pathway. American Journal of Physiology. Renal Physiology, 295(1), F128-F136.
• Naganawa, T., Xiao, L., Coffin, J., Doetschman, T., Sabbieti, M., Agas, D., & Hurley, M. (2008). Reduced expression and function of bone morphogenetic protein-2 in bones of Fgf2 null mice. Journal of Cell Biochemistry, 103(6), 1975-1988. PMID: 17955502.
• Prasad, V., Bodi, I., Meyer, J., Wang, Y., Ashraf, M., Engle, S., Doetschman, T., Sisco, K., Nieman, M., Miller, M., Lorenz, J., & Shull, G. (2008). Impaired cardiac contractility in mice lacking both the AE3 Cl-/. Journal of Biological Chemistry, 283(46), 31303-31314.
• Saxena, V., Lienesch, D., Zhou, M., Bommireddy, R., Azhar, M., Doetschman, T., & Singh, R. (2008). Dual roles of immunoregulatory cytokine TGF-beta in the pathogenesis of autoimmunity-mediated organ damage. Journal of Immunology, 180(3), 1903-1912.
• Gawenis, L., Bradford, E., Prasad, V., Lorenz, J., Simpson, J., Clarke, L., Woo, A., Grisham, C., Sanford, L., Doetschman, T., Miller, M., & Shull, G. (2007). Colonic Anion Secretory Defects and Metabolic Acidosis in Mice Lacking the NBC1 Formula Cotransporter. Journal of Biological Chemistry, 282(12), 9042-9052.
• House, S., Melhorn, S., Newman, G., Doetschman, T., & Schultz, J. J. (2007). The protein kinase C pathway mediates cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2. American Journal of Physiology. Heart and Circulatory Physiology, 293(1), H354-H365.
• Kaiser, S., Park, Y., Franklin, J., Halberg, R., Yu, M., Jessen, W., Freudenberg, J., Chen, X., Haigis, K., Jegga, A., Kong, S., Sakthivel, B., Xu, H., Reichling, T., Azhar, M., Boivin, G., Roberts, R., Bissahoyo, A., Gonzales, F., , Bloom, G., et al. (2007). Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biology, 8(7), R131.
• Liao, S., Porter, D., Scott, A., Newman, G., Doetschman, T., & Schultz, J. J. (2007). The cardioprotective effect of the low molecular weight isoform of fibroblast growth factor-2: the role of JNK signaling. Journal of Molecular and Cellular Cardiology, 42(1), 106-120.
• Makwana, M., Jones, L., Cuthill, D., Heuer, H., Bohatschek, M., Hristova, M., Friedrichsen, S., Ormsby, I., Bueringer, D., Koppius, A., Bauer, K., Doetschman, T., & Raivich, G. (2007). Endogenous transforming growth factor beta1 suppresses inflammation and promotes survival in adult CNS. Journal of Neuroscience, 27(42), 11201-11213..
• Okunade, G., Miller, M., Azhar, M., Andringa, A., Sanford, L., Doetschman, T., Prasad, V., & Shull, G. (2007). Loss of the Atp2c1 secretory pathway Ca(2+)-ATPase (SPCA1) in mice causes Golgi stress, apoptosis, and midgestational death in homozygous embryos and squamous cell tumors in adult heterozygotes. Journal of Biological Chemistry, 282(36), 26517-26527.
• Bommireddy, R., Pathak, L., Martin, J., Ormsby, I., Engle, S., Boivin, G., Babcock, G., Eriksson, A., Singh, R., & Doetschman, T. (2006). Self-antigen recognition by TGF beta1-deficient T cells causes their activation and systemic inflammation. Lab Invest, 86(10), 1008-1019.
• Fontaine, V., Filipe, C., Werner, N., Gourdy, P., Billon, A., Garmy-Susini, B., Brouchet, L., Bayard, F., Prats, H., Doetschman, T., Nickenig, G., & Arnal, J. (2006). Essential role of bone marrow fibroblast growth factor-2 in the effect of estradiol on reendothelialization and endothelial progenitor cell mobilization. American Journal of Pathology, 169(5), 1855-1862.
• Hurley, M., Okada, Y., Xiao, L., Tanaka, Y., Ito, M., Okimoto, N., Nakamura, T., Rosen, C., Doetschman, T., & Coffin, J. (2006). Impaired bone anabolic response to parathyroid hormone in Fgf2-/- and Fgf2+/- mice. Biochemical and Biophysical Research Communications, 341(4), 989-994.
• Chikama, T., Hayashi, Y., Liu, C., Terai, N., Terai, K., Kao, C., Wang, L., Hayashi, M., Nishida, T., Sanford, P., Doetschman, T., & Kao, W. (2005). Characterization of tetracycline-inducible bitransgenic Krt12rtTA/+/tet-O-LacZ mice. Investigative Ophthalmology and Visual Sciences, 46(6), 1966-1972.
• Gawenis, L., Greeb, J., Prasad, V., Grisham, C., Sanford, L., Doetschman, T., Andringa, A., Miller, M., & Shull, G. (2005). Impaired gastric acid secretion in mice with a targeted disruption of the NHE4 Na+/H+ exchanger. Journal of Biological Chemistry, 280(13), 12781-12789.
• House, S., Branch, K., Newman, G., Doetschman, T., & Schultz, J. J. (2005). Cardioprotection induced by cardiac-specific overexpression of fibroblast growth factor-2 is mediated by the MAPK cascade. American Journal of Physiology. Heart and Circulatory Physiology, 289(5), H2167-H2175.
• Bommireddy, R., Engle, S., Ormsby, I., Boivin, G., Babcock, G., & Doetschman, T. (2004). Elimination of both CD4+ and CD8+ T cells but not B cells eliminates inflammation and prolongs the survival of TGFbeta1-deficient mice. Cellular Immunology, 232(1-2), 96-104.
• Garmy-Susini, B., Delmas, E., Gourdy, P., Zhou, M., Bossard, C., Bugler, B., Bayard, F., Krust, A., Prats, A., Doetschman, T., Prats, H., & Arnal, J. (2004). Role of fibroblast growth factor-2 isoforms in the effect of estradiol on endothelial cell migration and proliferation. Circulation Research, 94, 1301-1309.
• Gawenis, L., Ledoussal, C., Judd, L., Prasad, V., Alper, S., Stuart-Tilley, A., Woo, A., Grisham, C., Sanford, L., Doetschman, T., Miller, M., & Shull, G. (2004). Mice with a targeted disruption of the AE2 Cl-/HCO3- exchanger are achlorhydric. Journal of Biological Chemistry, 279, 30531-30539.
• Molin, D., Poelmann, R., DeRuiter, M., Azhar, M., Doetschman, T., & Gittenberger-de Groot, A. (2004). Transforming growth factor beta-SMAD2 signaling regulates aortic arch innervation and development. Circulation Research, 95(11), 1109-1117.
• Okunade, G., Miller, M., Pyne, G., Sutliff, R., O'Connor, K., Neumann, J., Andringa, A., Miller, D., Prasad, V., Doetschman, T., Paul, R., & Shull, G. (2004). Targeted Ablation of Plasma Membrane Ca2+-ATPase (PMCA) 1 and 4 Indicates a Major Housekeeping Function for PMCA1 and a Critical Role in Hyperactivated Sperm Motility and Male Fertility for PMCA4. Journal of Biological Chemistry, 279, 33742-33750.
• Poelmann, R., Jongbloed, M., Molin, D., Fekkes, M., Wang, Z., Fishman, G., Doetschman, T., Azhar, M., & Gittenberger-de Groot, A. (2004). The neural crest is contiguous with the cardiac conduction system in the mouse embryo: a role in induction?. Anatomical Embryology, 208(5), 389-393.
• Tanaka, T., Saika, S., Ohnishi, Y., Ooshima, A., McAvoy, J., Liu, C., Azhar, M., Doetschman, T., & Kao, W. (2004). Fibroblast growth factor 2: roles of regulation of lens cell proliferation and epithelial-mesenchymal transition in response to injury. Molecular Vision, 10, 462-467.
• Boivin, G., Washington, K., Yang, K., Ward, J., Pretlow, T., Russell, R., Besselsen, D., Godfrey, V., Doetschman, T., Dove, W., Pitot, H., Halberg, R., Itzkowitz, S., Groden, J., & Coffey, R. (2003). Pathology of mouse models of intestinal cancer: Consensus report and recommendations. Gastroenterology, 124(3), 762-777. PMID12612914.
• Bommireddy, R., Ormsby, I., Yin, M., Boivin, G., Babcock, G., & Doetschman, T. (2003). TGF beta 1 inhibits Ca2+-calcineurin-mediated activation in thymocytes. Journal of Immunology, 170(7), 3645-3652.
• Bommireddy, R., Saxena, V., Ormsby, I., Yin, M., Boivin, G., Babcock, G., Singh, R., & Doetschman, T. (2003). TGF-beta1 regulates lymphocyte homeostasis by preventing activation and subsequent apoptosis of peripheral lymphocytes. Journal of Immunology, 170(9), 4612-4622. PMC2291527.
• House, S., Bolte, C., Zhou, M., Doetschman, T., Klevitsky, R., Newman, G., & Schultz, J. J. (2003). Cardiac-specific overexpression of fibroblast growth factor-2 protects against myocardial dysfunction and infarction in a murine model of low-flow ischemia. Circulation, 108(25), 3140-3148.
• Okada, Y., Montero, A., Zhang, X., Sobue, T., Lorenzo, J., Doetschman, T., Coffin, J., & Hurley, M. (2003). Impaired osteoclast formation in bone marrow cultures of Fgf2 null mice in response to parathyroid hormone. Journal of Biological Chemistry, 278(23), 21258-21266.
• Skelton, M., Ponniah, S., Wang, D., Doetschman, T., Vorhees, C., & Pallen, C. (2003). Protein tyrosine phosphatase alpha (PTPalpha) knockout mice show deficits in Morris water maze learning, decreased locomotor activity, and decreases in anxiety. Brain Research, 984(1-2), 1-10.
• Engle, S., Ormsby, I., Pawlowski, S., Boivin, G., Croft, J., Balish, E., & Doetschman, T. (2002). Elimination of colon cancer in germ-free Transforming Growth Factor beta 1-deficient mice. Cancer Research, 62(22), 6362-6366.
• Lorenz, J., Baird, N., Judd, L., Noonan, W., Andringa, A., Doetschman, T., Manning, P., Liu, L., Miller, M., & Shull, G. (2002). Impaired renal NaCl absorption in mice lacking the ROMK potassium channel, a model for type II Bartter's syndrome. Journal of Biological Chemistry, 277(40), 37871-37880.
• Molin, D., DeRuiter, M., Wisse, L., Azhar, M., Doetschman, T., Poelmann, R., & Gittenberger-de Groot, A. (2002). Altered apoptosis pattern during pharyngeal arch artery remodelling is associated with aortic arch malformations in Tgfbeta2 knock-out mice. Cardiovascular Research, 56(2), 312-322.
• Paradis, H., Liu, C., Saika, S., Azhar, M., Doetschman, T., Good, W., Nayak, R., Laver, N., Kao, C., Kao, W., & Gendron, R. (2002). Tubedown-1 in remodeling of the developing vitreal vasculature in vivo and regulation of capillary outgrowth in vitro. Developmental Biology, 249(1), 140.
• Pietri, L., Bloch-Faure, M., Belair, M., Sanford, L., Doetschman, T., Menard, J., Bruneval, P., & Meneton, P. (2002). Altered renin synthesis and secretion in the kidneys of heterozygous mice with a null mutation in the TGF-beta(2) gene. Exp Nephrol, 10(5-6), 374-382.
• Schultz, J. J., Witt, S., Glascock, B., Nieman, M., Reiser, P., Nix, S., Kimball, T., & Doetschman, T. (2002). TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. Journal of Clinical Investigation, 109(6), 787-796.
• Shao, C., Yin, M., Deng, L., Stambrook, P., Doetschman, T., & Tischfield, J. (2002). Loss of heterozygosity and point mutation at Aprt locus in T cells and fibroblasts of Pms2-/- mice.. Oncogene, 21, 2840-2845.
• Sullivan, C., Doetschman, T., & Hoying, J. (2002). Targeted disruption of the Fgf2 gene does not affect vascular growth in the mouse ischemic hindlimb. Journal of Applied Physiology, 93(6), 2009-2017.
• Bartram, U., Molin, D., Wisse, L., Mohamad, A., Sanford, L., Doetschman, T., Speer, C., Poelmann, R., & Gittenberger-de, G. A. (2001). Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in Tgfb2 knockout mice.. Circulation, 103(22), 2745-2752.
• Krane, C., Melvin, J., Nguyen, H., Richardson, L., Towne, J., Doetschman, T., & Menon, A. (2001). Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation.. Journal of Biological Chemistry, 276(26), 23413-23420.
• Meneton, P., Bloch-Faure, M., Hagege, A., Ruetten, H., Huang, W., Bergaya, S., Ceiler, D., Gehring, D., Martins, I., Salmon, G., Boulanger, C., Nussberger, J., Crozatier, B., Gasc, J., Heudes, D., Bruneval, P., Doetschman, T., Menard, J., & Alhenc-Gelas, F. (2001). Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice. Proceedings of the National Academy of Sciences, 98(5), 2634-2639.
• Saika, S., Liu, C., Azhar, M., Sanford, L., Doetschman, T., Gendron, R., Kao, C., & Kao, W. (2001). TGFbeta2 in Corneal Morphogenesis during Mouse Embryonic Development.. Dev Biol, 240, 419-432.
• Sanford, L., Kallapur, S., Ormsby, I., & Doetschman, T. (2001). Influence of genetic background on knockout mouse phenotypes.. Methods in Molecular Biology, 158, 217-225.
• Thomas, R., Belsito, D., Huang, C., Chen, L. L., Ormsby, I., Simmons, W., Cowin, P., Shaw, J., Doetschman, T., & Thorbecke, G. (2001). Appearance of Langerhans cells in the epidermis of Tgfb1(-/-) SCID mice: paracrine and autocrine effects of transforming growth factor-beta 1 and -beta 2(1).. J Invest Dermatol, 117, 1574-1580.
• Crowe, M., Doetschman, T., & Greenhalgh, D. (2000). Delayed wound healing in immunodeficient TGF-beta1 knockout mice. J Invest Dermatol., 115(1), 3-11.
• Montero, A., Okada, Y., Tomita, M., Ito, M., Tsurukami, H., Nakamura, T., Doetschman, T., Coffin, J., & Hurley, M. (2000). Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. Journal of Clinical Investigation, 105(8), 1085-1093.
• Spicer, Z., Miller, M., Andringa, A., Riddle, T., Duffy, J., Doetschman, T., & Shull, G. (2000). Stomachs of mice lacking the gastric H,K-ATPase alpha -subunit have achlorhydria, abnormal parietal cells, and ciliated metaplasia.. J Biol Chem, 275(28), 21555-21565.
• Doetschman, T. (1999). Interpretation of phenotype in genetically engineered mice.. Laboratory Animal Science, 49(2), 137-143.
• Engle, S., Hoying, J., Boivin, G., Ormsby, I., Gartside, P., & Doetschman, T. (1999). Transforming growth factor beta1 suppresses nonmetastatic colon cancer at an early stage of tumorigenesis. Cancer Research, 59(14), 3379-3386.
• Flagella, M., Clarke, L., Miller, M., Erway, L., Giannella, R., Andringa, A., Gawenis, L., Kramer, J., Duffy, J., Doetschman, T., Lorenz, J., Yamoah, E., Cardell, E., & Shull, G. (1999). Mice Lacking the Basolateral Na-K-2Cl Cotransporter Have Impaired Epithelial Chloride Secretion and Are Profoundly Deaf. Journal of Biological Chemistry, 274(38), 26946-26955.
• Foitzik, K., Paus, R., Doetschman, T., & Paolo, D. G. (1999). The TGF-beta2 Isoform Is Both a Required and Sufficient Inducer of Murine Hair Follicle Morphogenesis. Developmental Biology, 212(2), 278-289.
• Hoying, J., Yin, M., Diebold, R., Ormsby, I., Becker, A., & Doetschman, T. (1999). Transforming growth factor beta1 enhances platelet aggregation through a non-transcriptional effect on the fibrinogen receptor. Journal of Biological Chemistry, 274(43), 31008-31013.
• Kallapur, S., Ormsby, I., & Doetschman, T. (1999). Strain dependency of TGFbeta1 function during embryogenesis. Molecular Reproduction and Development, 52(4), 341-349.
• Li, J., Foitzik, K., Calautti, E., Baden, H., Doetschman, T., & Dotto, G. (1999). TGF-beta3, but not TGF-beta1, protects keratinocytes against 12-O- tetradecanoylphorbol-13-acetate-induced cell death in vitro and in vivo. Journal of Biological Chemistry, 274(7), 4213-4219.
• Periasamy, M., Reed, T., Liu, L., Ji, Y., Loukianov, E., Paul, R., Nieman, M., Riddle, T., Duffy, J., Doetschman, T., Lorenz, J., & Shull, G. (1999). Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. Journal of Biological Chemistry, 274(4), 2556-2562.
• Raivich, G., Jones, L., Werner, A., Bluthmann, H., Doetschmann, T., & Kreutzberg, G. (1999). Molecular signals for glial activation: pro- and anti-inflammatory cytokines in the injured brain. Acta Neurochirurgica, 73:21-30., 21-30.
• Schultz, J., Witt, S., Nieman, M., Reiser, P., Engle, S., Zhou, M., Pawlowski, S., Lorenz, J., Kimball, T., & Doetschman, T. (1999). Fibroblast growth factor-2 mediates pressure-induced hypertrophic response. Journal of Clinical Investigation, 104(6), 709-719.
• Vaccarino, F., Schwartz, M., Raballo, R., Nilsen, J., Rhee, J., Zhou, M., Doetschman, T., Coffin, J., Wyland, J., & Hung, Y. (1999). Changes in cerebral cortex size are governed by fibroblast growth factor during embryogenesis. Nature Neuroscience, 2(3), 246-253.
• Barone, K., Tolarova, D., Ormsby, I., Doetschman, T., & Michael, J. (1998). Induction of oral tolerance in TGF-beta 1 null mice. Journal of Immunology, 161(1), 154-160.
• Kozel, P., Friedman, R., Erway, L., Yamoah, E., Liu, L., Riddle, T., Duffy, J., Doetschman, T., Miller, M., Cardell, E., & Shull, G. (1998). Balance and hearing deficits in mice with a null mutation in the gene encoding plasma membrane Ca2+-ATPase isoform 2. Journal of Biological Chemistry, 273(30), 18693-18696.
• Lidral, A., Romitti, P., Basart, A., Doetschman, T., Leysens, N., Daack-Hirsch, S., Semina, E., Johnson, L., Machida, J., Burds, A., Parnell, T., Rubenstein, J., & Murray, J. (1998). Association of MSX1 and TGFB3 with nonsyndromic clefting in humans. American Journal of Human Genetics, 63(2), 557-568.
• Meneton, P., Schultheis, P., Greeb, J., Nieman, M., Liu, L., Clarke, L., Duffy, J., Doetschman, T., Lorenz, J., & Shull, G. (1998). Increased sensitivity to K+ deprivation in colonic H,K-ATPase-deficient mice. Journal of Clinical Investigation, 101(3), 536-542.
• Paradies, N., Sanford, L., Doetschman, T., & Friedman, R. (1998). Developmental expression of the TGF betas in the mouse cochlea.. Mechanisms of Development, 79, 165-168.
• Schultheis, P., Clarke, L., Meneton, P., Harline, M., Boivin, G., Stemmermann, G., Duffy, J., Doetschman, T., Miller, M., & Shull, G. (1998). Targeted disruption of the murine Na+/H+ exchanger isoform 2 gene causes reduced viability of gastric parietal cells and loss of net acid secretion. Journal of Clinical Investigation, 101(6), 1243-1253.
• Schultheis, P., Clarke, L., Meneton, P., Miller, M., Soleimani, M., Gawenis, L., Riddle, T., Duffy, J., Doetschman, T., Wang, T., Giebisch, G., Aronson, P., Lorenz, J., & Shull, G. (1998). Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nature Genetics, 19(3), 282-285.
• Schultheis, P., Lorenz, J., Meneton, P., Nieman, M., Riddle, T., Flagella, M., Duffy, J., Doetschman, T., Miller, M., & Shull, G. (1998). Phenotype resembling Gitelman's syndrome in mice lacking the apical Na+-Cl- cotransporter of the distal convoluted tubule. Journal of Biological Chemistry, 273(44), 29150-29155.
• Zhou, M., Sutliff, R., Paul, R., Lorenz, J., Hoying, J., Haudenschild, C., Yin, M., Coffin, J., Kong, L., Kranias, E., Luo, W., Boivin, G., Duffy, J., Pawlowski, S., & Doetschman, T. (1998). Fibroblast growth factor 2 control of vascular tone. Nature Medicine, 4(2), 201-207.
• Boivin, G., Ormsby, I., Jones-Carson, J., O'Toole, B., & Doetschman, T. (1997). Germ-free and barrier-raised TGF beta 1-deficient mice have similar inflammatory lesions. Transgenic Research, 6(3), 197-202.
• Davis, M., Zhou, M., Ali, S., Coffin, J., Doetschman, T., & Dorn, G. (1997). Intracrine and autocrine effects of basic fibroblast growth factor in vascular smooth muscle cells. Journal of Molecular and Cellular Cardiology, 29(4), 1061-1072.
• Kumar, A., Crawford, K., Close, L., Madison, M., Lorenz, J., Doetschman, T., Pawlowski, S., Duffy, J., Neumann, J., Robbins, J., Boivin, G., O'Toole, B., & Lessard, J. (1997). Rescue of cardiac alpha-actin-deficient mice by enteric smooth muscle gamma-actin. Proceedings of the National Academy of Sciences, 94(9), 4406-4411.
• Lightfoot, P., Swisher, R., Coffin, J., Doetschman, T., & German, R. (1997). Ontogenetic limb bone scaling in basic fibroblast growth factor (FGF-2) transgenic mice. Growth, Development, and Aging, 61(3-4), 127-139.
• Liu, L., Paul, R., Sutliff, R., Miller, M., Lorenz, J., Pun, R., Duffy, J., Doetschman, T., Kimura, Y., MacLennan, D., Hoying, J., & Shull, G. (1997). Defective endothelium-dependent relaxation of vascular smooth muscle and endothelial cell Ca2+ signaling in mice lacking sarco(endo)plasmic reticulum Ca2+-ATPase isoform 3. Journal of Biological Chemistry, 272(48), 30538-30545.
• Ng, W., Doetschman, T., Robbins, J., & Lessard, J. (1997). Muscle isoactin expression during in vitro differentiation of murine embryonic stem cells.. Pediatric Research, 41(2), 285-292.
• Sanford, L., Ormsby, I., Gittenberger-de Groot, A., Sariola, H., Friedman, R., Boivin, G., Cardell, E., & Doetschman, T. (1997). TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development, 124(13), 2659-2670.
• Boivin, G., Molina, J., Ormsby, I., Stemmermann, G., & Doetschman, T. (1996). Gastric lesions in transforming growth factor beta-1 heterozygous mice. Laboratory Investigation, 74(2), 513-518.
• Fontaine, R., Gossett, R., Schroeder, F., O'Toole, B., Doetschman, T., & Kier, A. (1996). Liver and intestinal fatty acid binding proteins in control and TGF beta 1 gene targeted deficient mice. Molecular and Cell Biochemistry, 159(2), 149-153.
• Jones, W., Grupp, I., Doetschman, T., Grupp, G., Osinska, H., Hewett, T., Boivin, G., Gulick, J., Ng, W., & Robbins, J. (1996). Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart. Journal of Clinical Investigation, 98(8), 1906-1917.
• Kao, W., Liu, C., Converse, R., Shiraishi, A., Kao, C., Ishizaki, M., Doetschman, T., & Duffy, J. (1996). Keratin 12-deficient mice have fragile corneal epithelia. Investigative Ophthalmology & Visual Science, 37(13), 2572-2584.
• Ludwig, D., Stringer, J., Wight, D., Doetschman, T., & Duffy, J. (1996). FLP-mediated site-specific recombination in microinjected murine zygotes. Transgenic Research, 5(6), 385-395.
• Luo, W., Wolska, B., Grupp, I., Harrer, J., Haghighi, K., Ferguson, D., Slack, J., Grupp, G., Doetschman, T., Solaro, R., & Kranias, E. (1996). Phospholamban gene dosage effects in the mammalian heart. Circulation Research, 78(5), 839-847.
• Boivin, G., O'Toole, B., Orsmby, I., Diebold, R., Eis, M., Doetschman, T., & Kier, A. (1995). Onset and progression of pathological lesions in transforming growth factor-beta 1-deficient mice. American Journal of Pathology, 146(1), 276-288.
• Brown, R., Ormsby, I., Doetschman, T., & Greenhalgh, D. (1995). Wound healing in the transforming growth factor-beta1-deficient mouse. Wound Repair and Regeneration, 3, 25-36.
• Coffin, J., Florkiewicz, R., Neumann, J., Mort-Hopkins, T., Dorn, G., Lightfoot, P., German, R., Howles, P., Kier, A., O'Toole, B., & ., . (1995). Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. Molecular Biology of the Cell, 6(12), 1861-1873.
• Diebold, R., Eis, M., Yin, M., Ormsby, I., Boivin, G., Darrow, B., Saffitz, J., & Doetschman, T. (1995). Early-onset multifocal inflammation in the transforming growth factor beta 1-null mouse is lymphocyte mediated. Proceedings of the National Academy of Sciences, 92(26), 12215-12219.
• Guenard, V., Rosenbaum, T., Gwynn, L., Doetschman, T., Ratner, N., & Wood, P. (1995). Effect of transforming growth factor-beta 1 and -beta 2 on Schwann cell proliferation on neurites. GLIA, 13(4), 309-318.
• Proetzel, G., Pawlowski, S., Wiles, M., Yin, M., Boivin, G., Howles, P., Ding, J., Ferguson, M., & Doetschman, T. (1995). Transforming growth factor-beta 3 is required for secondary palate fusion. Nature Genetics, 11(4), 409-414.
• Luo, W., Grupp, I., Harrer, J., Ponniah, S., Grupp, G., Duffy, J., Doetschman, T., & Kranias, E. (1994). Targeted ablation of the phospholamban gene is associated with markedly enhanced myocardial contractility and loss of beta- agonist stimulation. Circ Res, 75(3), 401-409.
• Shull, M., & Doetschman, T. (1994). Transforming growth factor-beta 1 in reproduction and development.. Molecular Reproduction & Development, 39(2), 239-246.
• Askew, G., Doetschman, T., & Lingrel, J. (1993). Site-directed point mutations in embryonic stem cells: a gene-targeting tag-and-exchange strategy. Molecular and Cellular Biology, 13(7), 4115-4124.
• Muthuchamy, M., Pajak, L., Howles, P., Doetschman, T., & Wieczorek, D. (1993). Developmental analysis of tropomyosin gene expression in embryonic stem cells and mouse embryos. Molecular and Cellular Biology, 13(6), 3311-3323.
• Shaw-White, J., Denko, N., Albers, L., Doetschman, T., & Stringer, J. (1993). Expression of the lacZ gene targeted to the HPRT locus in embryonic stem cells and their derivatives.. Transgenic Research, 2(1), 1-13.
• Ganim, J., Luo, W., Ponniah, S., Grupp, I., Kim, H., Ferguson, D., Kadambi, V., Neumann, J., Doetschman, T., & Kranias, E. (1992). Mouse phospholamban gene expression during development in vivo and in vitro. Circulation Research, 71(5), 1021-1030.
• Shull, M., Ormsby, I., Kier, A., Pawlowski, S., Diebold, R., Yin, M., Allen, R., Sidman, C., Proetzel, G., Calvin, D., & Doetschman, T. (1992). Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature, 359(6397), 693-699.
• Sanchez, A., Jones, W., Gulick, J., Doetschman, T., & Robbins, J. (1991). Myosin heavy chain gene expression in mouse embryoid bodies. An in vitro developmental study. Journal of Biological Chemistry, 266(33), 22419-22426.
• Robbins, J., Gulick, J., Sanchez, A., Howles, P., & Doetschman, T. (1990). Mouse embryonic stem cells express the cardiac myosin heavy chain genes during development in vitro. Journal of Biological Chemistry, 265(20), 11905-11909.
• Doetschman, T., Maeda, N., & Smithies, O. (1988). Targeted mutation of the Hprt gene in mouse embryonic stem cells. Proceedings of the National Academy of Sciences, 85(22), 8583-8587.
• Doetschman, T., Williams, P., & Maeda, N. (1988). Establishment of hamster blastocyst-derived embryonic stem (ES) cells. Developmental Biology, 127(1), 224-227.
• Risau, W., Sariola, H., Zerwes, H., Sasse, J., Ekblom, P., Kemler, R., & Doetschman, T. (1988). Vasculogenesis and angiogenesis in embryonic-stem-cell-derived embryoid bodies. Development, 102(3), 471-478.
• Boller, K., Kemler, R., Baribault, H., & Doetschman, T. (1987). Differential distribution of cytokeratins after microinjection of anti-cytokeratin monoclonal antibodies. European Journal of Cell Biology, 43(3), 459-468.
• Doetschman, T., Gregg, R., Maeda, N., Hooper, M., Melton, D., Thompson, S., & Smithies, O. (1987). Targetted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature, 330(6148), 576-578.
• Doetschman, T., Gossler, A., Serfling, E., Schaffner, W., Marcu, K., Stanton, L., & Kemler, R. (1986). Introduction of genes into mouse embryonic stem cells. Progress in Clinical Biology Research, 217A, 47-50.
• Gossler, A., Doetschman, T., Korn, R., Serfling, E., & Kemler, R. (1986). Transgenesis by means of blastocyst-derived embryonic stem cell lines. Proceedings of the National Academy of Sciences, 83(23), 9065-9069.
• Doetschman, T., Eistetter, H., Katz, M., Schmidt, W., & Kemler, R. (1985). The in vitro development of blastocyst-derived embryonic stem cell lines: formation of visceral yolk sac, blood islands and myocardium.. Journal of Embryology and Experimental Morphology, 87, 27-45.
• Doetschman, T., & Eppenberger, H. (1984). Comparison of M-line and other myofibril components during reversible phorbol ester treatment.. European Journal of Cell Biology, 33(2), 265-274.
• Grove, B., Kurer, V., Lehner, C., Doetschman, T., Perriard, J., & Eppenberger, H. (1984). A new 185,000-dalton skeletal muscle protein detected by monoclonal antibodies. Journal of Cell Biology, 98(2), 518-524.
• Ernst, M., Eppenberger, H., & Doetschman, T. (1983). Initial appearance of myomesin in differentiating muscle cells. Cell Differentiation, 13(4), 319-323.
• Wallimann, T., Doetschman, T., & Eppenberger, H. (1983). Novel staining pattern of skeletal muscle M-lines upon incubation with antibodies against MM-creatine kinase. Journal of Cell Biology, 96(6), 1772-1779.
• Eppenberger, H., Strehler, E., Doetschman, T., Rosenberg, U., Perriard, J., & Wallimann, T. (1982). Developmental history of the two M-line proteins MM-creatine kinase and myomesin during myogenesis.. Progress in Clinical Biology Research, 85 Pt B:381-9, 381-389.
• Doetschman, T., & Jewett, J. (1981). The contribution of cell death to medium-released fractions of cell cultures. In Vitro, 17(2), 178-184.
• Doetschman, T. (1980). Cell surface turnover and shedding of fucosyl-glycoprotein in L6 cells. Cell Biology International Reports, 4(4), 379-390.
• Doetschman, T. (1980). The effects of Con A on cell surface shedding in cell cultures. Journal of Cell Science, 46, 221-234.
• Doetschman, T., Dym, H., Siegel, E., & Heywood, S. (1980). Myoblast stored myosin heavy chain transcripts are precursors to the myotube polysomal myosin heavy chain mRNAs. Differentiation, 16(3), 149-162.
• Doetschman, T., Havaranis, A., & Herrmann, H. (1975). Insulin binding to cells of several tissues of the early chick embryo. Developmental Biology, 47(1), 228-232.
• Herrmann, H., Havaranis, A., & Doetschman, T. (1975). Incorporation of fucose and glucosamine into cell bound and medium released macromolecules.. Journal of Cell Physiology, 85(3), 557-568.

Presentations

• Doetschman, T. C. (2015, March 10). Expression Analysis from Single Nucleus. Cancer Biology Program.
• Doetschman, T. C. (2013, September). TGFbeta2 in Heart Valve Remodeling. Les Treilles Conference on TGFbeta in Extracellular Matrix Function. Les Treilles, France: Fondation des Treilles.
  More info

  One of 17 participants on TGFbeta in the functional roles of extracellular matrix.
• Doetschman, T. C. (2014, March). Sex-specific roles of FGF2 isoforms in heart development and remodeling. Gordon Conference. Ventura, CA: Gordon Research Conferences.

Reviews

• Doetschman, T., & Azhar, M. (2012. Cardiac-specific inducible and conditional gene targeting in mice(pp 1498-1512).
• Doetschman, T. (2011. GI GEMs: genetically engineered mouse models of gastrointestinal disease(pp 380-385).
• Bommireddy, R., & Doetschman, T. (2007. TGFbeta1 and Treg cells: alliance for tolerance(pp 492-501).
• Bommireddy, R., & Doetschman, T. (2004. TGF-beta, T-cell tolerance and anti-CD3 therapy(pp 3-9).
• Azhar, M., Schultz, J. J., Grupp, I., Dorn, G., Meneton, P., Molin, D., Gittenberger-de Groot, A., & Doetschman, T. (2003. Transforming growth factor beta in cardiovascular development and function(pp 391-407).
• Doetschman, T. (1998. Laboratory Protocols for Conditional Gene Targeting(p. 383).
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  Book Review. "Laboratory Protocols for Conditional Gene Targeting" Raul M. Torres & Ralf Kühn.
• Doetschman, T., Shull, M., Kier, A., & Coffin, J. (1993. Embryonic stem cell model systems for vascular morphogenesis and cardiac disorders. [Review](pp 618-629).
• Koller, B., & Smithies, O. (1992. Altering genes in animals by gene targeting.(pp 705-730).
• Doetschman, T. (1991. Gene targeting in embryonic stem cells. [Review](pp 89-101).

Others

• Doetschman T, . (2010, 01/2010). In Memoriam: Heinz Herrmann, 1911-2009. American Society of Cell Biology Newsletter.