Andres Hernandez-Garcia
Picture
Andres Hernandez-Garcia
Postdoctoral Associate
Positions
- Postdoctoral Associate
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Molecular and Human Genetics/ D. Scott Lab
Baylor College of Medicine
Houston, TX US
- INSTRUCTOR
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SURGERY
GENERAL SURGERY
Baylor College of Medicine
HOUSTON, Texas United States
- Distinguished University Professor
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College of Medicine
Unidad Torreon
Faculty of Medicine, Universidad Autónoma de Coahuila, México.
Torreon, Coahuila Mexico
Professor of Genetics and Professor of Medicine (Embryology). Founder of the Biomedical Research Center at Universidad Autónoma de Coahuila, México. Full time Professor Category “C” at Faculty of Medicine, Universidad Autónoma de Coahuila, Dean of the College of Medicine, Biomedical Research Center, General University Hospital and Pediatrics University Hospital of the Universidad Autónoma de Coahuila during the period of March, 1992 to March, 1996. Founder, Chairman and Consultant of Genetics Department at Faculty of Medicine and University Hospitals of Torreón, Coah. México.
- Dean of College of Medicine.
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Universidad Autónoma de Coahuila.
Torreon, Coahuila Mexico
Working closely with subdeans of University Hospitals and Biomedical Research Center and other members of senior leadership, my primary responsibility was to oversee all educational and administrative activities across the College and University Hospitals in alignment with the mission, vision and values of the Universidad Autonoma de Coahuila. The Dean of Medical School retains primary responsibility for all the educational programs, ensuring that all programs achieve the highest standards to prepare our trainees to be leaders in their respective fields. The major responsibility of the Dean of the College of Medicine Unidad Torreon of Universidad Autonoma de Coahuila shall be that of providing active leadership in the promotion, direction and support of the clinical, educational and research activities of the University, in the maintenance of a high level of morale among the faculty, and in the encouragement of the spirit of learning among the students. In addition the Dean shall have general and primary administrative responsibility for the different programs from the College, University Hospital and Biomedical Research Center.
- Dean of University General Hospital.
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Universidad Autónoma de Coahuila.
Torreon, Coahuila Mexico
- Dean of University Pediatric Hospital.
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Universidad Autónoma de Coahuila.
Torreon, Coahuila Mexico
- Dean Biomedical Research Center
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Universidad Autónoma de Coahuila.
Torreon, Coahuila Mexico
- Subdean of Centro De Investigación Biomédica.
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Universidad Autónoma de Coahuila.
Torreon, Coahuila Mexico
- Professor
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College of Chemistry
Unidad Cuautitlán Izcalli. Estado de México.
Universidad Nacional Autónoma de México.
México, D.F, Estado de México Mexico
Professor of Genetics
- Professor
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School of Psychology.
Instituto Superior de Ciencia y Tecnología de la Laguna (ISCYTAC).
Universidad La Salle Laguna.
Torreon, Coahuila Mexico
Professor of Genetics and Embryology professor of Psychoendocrinology
- Scientist Staff
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Molecular and Human Genetics.
Baylor College of Medicine
Houston, Texas United States
- Member
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Dan L Duncan Comprehensive Cancer Center
Baylor College of Medicine
Houston, Texas United States
- Scientist Staff
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Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas United States
Education
- PhD from Universidad Autonoma de Nuevo Leon (UANL)
- 10/2003 - Monterrey, Nuevo Leon Mexico
- Ph D. in Molecular Biology and Genetic Engineering Faculty of Medicine. Universidad Autónoma de Nuevo León. Period: 1998 to 2001. Monterrey. N.L. México. UANL. Registration Number: 133661. Registration Secretaría de Educación Pública: 4124807.
- MD from Universidad Autonoma de Coahuila (UAdeC)
- 05/1978 - Saltillo, Coahuila Mexico
- Medical Doctor Degree. Universidad Autónoma de Coahuila. May 3, 1978. Number 6444/218/V., Certificate/License Number: Registration S.S.A. number 506890. Date Degree Conferred: July 18, 1978.
- Residency at Instituto Nacional de Ciencias Medicas y Nutricion "Salvador Zubirán". INCMNSZ
- 05/1980 - Mexico, Distrito Federal Mexico
- Medical Genetics Degree Program of Specialty in Medical Genetics. Instituto Nacional de la Nutrición Salvador Zubirán., Universidad Nacional Autónoma de México. México, D. F. 1978 - 1980
- Postdoctoral Fellowship at Texas Children’s Hospital and Baylor College of Medicine.
- 07/2000 - HOUSTON, Texas United States
- Postdoctoral Research Fellow Department of Pediatric-Hematology/ Oncology, Texas Children’s Hospital and Baylor College of Medicine. Houston, Texas, U.S.A. October 5, 1998 to 31 July, 2000.
- Postdoctoral Fellowship at Department of Radiology/Radiation Oncology, Veterans Affairs Medical Center and Baylor College of Medicine
- 05/2001 - HOUSTON, Texas United States
- Postdoctoral Research Fellow Department of Radiology/Radiation Oncology, Veterans Affairs Medical Center and Baylor College of Medicine Houston, Texas, U.S.A. 1 August, 2000 to 31 May, 2001.
- Postdoctoral Training at BAYLOR COLLEGE OF MEDICINE
- 06/2009 - HOUSTON, Texas United States
- Postdoctoral Associate Department of Molecular and Human Genetics Baylor College of Medicine Houston, Texas, U.S.A. June 2009 to date
- Residency at Unidad de Investigación Biomédica IMSS. Centro Médico Nacional. México, D.F.
- 09/1978 - Mexico, Distrito Federal Mexico
Honors & Awards
- Award and prize during Cardiovascular Research Institute Symposium.
- Best Abstract Award at the 4th Annual Cardiovascular Research Institute Symposium. Baylor College of Medicine. February 4, 2016. Houston, TX. USA.
- Cardiovascular Research Institute. Baylor College of Medicine. (02/2016)
- Molecular Surgeon Young Investigador Award
- 2008 Molecular Surgeon Young Investigador Award. Michael E. DeBakey Department of Surgery. Baylor College of Medicine. Nineteenth Day of December 2008. Houston, TX. USA.
- Michael E. DeBakey Department of Surgery. Baylor College of Medicine. (12/2008)
- Award National System of Researchers (SNI)
- Consejo Nacional de Ciencia y Tecnología, México. (01/2006)
- Award in Health Sciences Research
- Award in Health Sciences Research UANL-2002 by the scientific work titled Preimmunization to adenoviruses may influence the therapeutic effectiveness and toxicity of adenoviral-mediated gene therapy for cancer. Universidad Autónoma de Nuevo León. Monterrey N. L, México. September 12, 2003.
- Universidad Autónoma de Nuevo León (09/2003)
- Award in Basic Sciences Research
- Award in Basic Sciences Research Universidad Autónoma de Nuevo León. Mexico.
- Universidad Autónoma de Nuevo León (09/1987)
- Award in Clinical Research
- Award in Clinical Research. (1988.) Universidad Autónoma de Nuevo León. Mexico.
- Universidad Autónoma de Nuevo León (09/1988)
- Academic achievement scholarship
- Granted of academic performance scholarship (1991, 92, 93, 94 and 95) Universidad Autónoma de Coahuila and Secretaría de Educación Pública.
- Universidad Autónoma de Coahuila. (09/1991 - 08/1995)
- MIGUEL RAMOS ARIZPE. Medal for Academic Worth
- Granted of MIGUEL RAMOS ARIZPE. Medal for Academic Worth Universidad Autónoma de Coahuila. Saltillo, Coah. Oct. 30, 1992.
- Universidad Autónoma de Coahuila. (10/1992)
- ASHG 2016 Annual Conference Poster Special Recognition Award.
- ASHG 2016 Annual Conference Poster Special Recognition Award. Title: “SOX7 deficiency impairs embryonic vasculogenesis and epithelial-to-mesenchymal transition during atrioventricular endocardial cushion development” which has been selected as a Reviewers' Choice Abstract, by the American Society of Human Genetics Conference Committee 2016 at Vancouver, Canada..
- American Society of Human Genetics (10/2016 - 10/2016)
- Down-regulation of Sox7 impairs epithelial-to-mesenchymal transition and endocardial cushion morphogenesis.
- Title: Down-regulation of Sox7 impairs epithelial-to-mesenchymal transition and endocardial cushion morphogenesis. ACCEPTED for a PLATFORM (oral) presentation at the 2018 American Society of Human Genetics Annual Meeting in San Diego, California from October 16-20, 2018. Presentation Type: PLATFORM (Oral Presentation) Session Number and Title: 30. Cardiac, Valvular, and Vascular Disorders Session Date: Wednesday, October 17 Session Time: 4:15 pm - 5:45 pm Presentation Time (10 minutes + 5 minutes QandA): 5:00 PM Abstract Title: Down-regulation of Sox7 impairs epithelial-to-mesenchymal transition and endocardial cushion morphogenesis. Abstract Program Number: 80 Location: San Diego Convention Center, 111 W Harbor Dr, San Diego, CA 92101 Room: Room 6D, Upper Level
- American Society of Human Genetics (10/2018)
- SOX7 ablation in endocardium results in downregulation of WNT4 and BMP2 and abnormal endocardial cushion development
- Reviewers' Choice Poster Special Recognition Award. Title: “SOX7 ablation in endocardium results in downregulation of WNT4 and BMP2 and abnormal endocardial cushion development”, abstract scored in the top 10% of posters abstracts
- 10/2019
Professional Statement
"He who masters the two sciences of clinical medicine and molecular medicine possess almost all that is necessary for opportune and effective diagnosis and treatment. Conversely, he who knows only one of these two sciences will be prone to multiple mistakes, because in the study of disease, molecular medicine is as valuable as the clinical sciences."Websites
Best Abstract Awards from the Fourth Annual Symposium 2016
Congratulations to the 6 Best Abstract winners from the Fourth Annual CVRI Symposium Feb. 4, 2016 at Baylor College of Medicine! Read more about it.
Houston, TX - Apr 14, 2016
One in 5,000 babies is born missing a small amount of genetic material from the tip of chromosome 1, a region called 1p36. Missing genes in the 1p36 region is a relatively common cause of intellectual disability. These children may also have delayed development, seizures, heart and kidney defects, and problems with vision and hearing. The number and severity of these medical conditions varies greatly among children with 1p36 deletions. Scientists think that one reason for this variability is that the genes that are missing from the 1p36 region are not the same in each individual. Knowing which genes are actually involved in the development of this syndrome would help physicians predict the type of medical conditions a child with a 1p36 deletion might encounter and would make it easier to create individualized care plans for these patients. In a paper published today in the American Journal of Human Genetics, a multidisciplinary team including Baylor College of Medicine researchers has determined that mutations in one gene, RERE, can cause many of the features associated with 1p36 deletions.
“This discovery is important for the parents of the children with this syndrome because it answers one of their most pressing questions, what are the problems that my child is likely to have?” said Dr. Daryl A. Scott, associate professor of molecular and human genetics and molecular physiology and biophysics at Baylor and one of the two senior authors of this report.
Scott worked closely with Dr. Elliot H. Sherr, the other senior author of the paper, Sherr’s team from the department of neurology at the University of California, San Francisco, and other physicians and scientists from around the world to identify 10 patients with mutations in RERE, which is located in the 1p36 region. These patients had medical problems that were very similar to those of patients in which dozens of 1p36 genes are deleted.
“We are the first to provide evidence that RERE mutations alone can cause developmental problems typical of 1p36 deletions. RERE is important in early development,” said Scott.
This discovery is the culmination of 10 years of research in mice and other animal models. Scott and colleagues demonstrated that, in mice, Rere mutations alone result in the animals having many of the characteristics observed in patients with 1p36 deletion syndrome. However, it was impossible to prove that RERE could play the same role in humans. “One of the big surprises of our paper is that just one gene can cause many of the problems observed when the tip of chromosome 1 is deleted,” said Scott. “We anticipate that this finding will be of particular interest to the parents in the 1p36 Deletion Support and Awareness group.”
In addition, the research is a boon to families of children with RERE mutations, who know for the first time the reason their children share this group of developmental disabilities.
“Just having an answer can be hugely beneficial for families,” said Sherr, a practicing neurologist who works closely with these patients and their families. “Of course, getting a genetic answer is just the first step, but for the longest time we didn’t even have that much. It gives these families hope that we can move forward.”
Sherr is also with the department of pediatrics at UCSF.
The next step in Scott’s research will be to focus on the role of RERE in the development of the brain, heart, eye and other organs.
The following researchers also contributed to these research: Brieana Fregeau, Department of Neurology, University of California, San Francisco; Bum Jun Kim, Andrés Hernández-García, Jill A. Rosenfeld, and Seema R. Lalani, Department of Molecular and Human Genetics, Baylor; Valerie K. Jordan, Department of Molecular Physiology and Biophysics, Baylor; Megan T. Cho, Rhonda E. Schnur, Kristin G. Monaghan, and Jane Juusola, GeneDx, Gaithersburg, MD; Elizabeth Bhoj and Elaine H. Zackai, Division of Genetics, Children’s Hospital of Philadelphia; Stephanie Sacharow, Division of Medical Genetics, Boston Children’s Hospital; Kristin Barañano, Department of Neurology, Johns Hopkins University School of Medicine; Danielle G.M. Bosch and Bert B.A. de Vries Department of Human genetics, Radboud University Medical Center, The Netherlands; Kristin Lindstrom, Philip James and Peggy Kulch, Division of Genetics and Metabolism, Phoenix Children’s Hospital; Dani?lle G.M. Bosch, Bartiméus Institute for the Visually Impaired, The Netherlands, and the Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, The Netherlands; Mieke M. van Haelst, Koen L.I. van Gassen and Ellen van Binsbergen, Department of Genetics, University Medical Center Utrecht, The Netherlands; A. James Barkovich, Department of Radiology, University of California, San Francisco; and Audrey Schroeder, division of genetics, University of Rochester Medical Center, Rochester, NY.
This work was supported by the National Institute of Neurological Disorders and Stroke grant R01 NS058721, The Netherlands Organization for Health Research and Development grant 912-12-109 and ODAS Stichting.
Sherr is a member of the clinical advisory board of Invitae and consults for Personalis. Cho, Schnur, Monaghan, and Juusola are all employees of GeneDx, which provides exome sequencing on a clinical basis. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from clinical laboratory testing conducted at Baylor Miraca Genetics Laboratories, which provides exome sequencing on a clinical basis.
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Selected Publications
- Beck TF, Campeau PM, Jhangiani SN, Gambin T, Li AH, Abo-Zahrah R, Jordan VK, Hernandez-Garcia A, Wiszniewski WK, Muzny D, Gibbs RA, Boerwinkle E, Lupski JR, Lee B, Reardon W, Scott DA. "FBN1 contributing to familial congenital diaphragmatic hernia.." Am J Med Genet A.. 2015 April ; 167 (4): 831-836.
- Fregeau B, Kim BJ, Hernández-García A, Jordan VK, James P, Kulch P, Lalani SR, van Haelst MM, van Gassen KL, van Binsbergen E, Barkovich AJ, Scott DA, Sherr EH. et al "De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions." Am J Hum Genet.. 2016 April 13; :
- Tackett BC, Sun H, Mei Y, Maynard JP, Cheruvu S, Mani A, Hernandez-Garcia A, Vigneswaran N, Karpen SJ, Thevananther S. "P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy.." Am J Physiol Gastrointest Liver Physiol.. 2014 December 1; 3007 (11): 1073-87.
- Zaveri HP, Beck TF, Hernández-García A, Shelly KE, Montgomery T, van Haeringen A, Anderlid BM, Patel C, Goel H, Houge G, Morrow BE, Cheung SW, Lalani SR, Scott DA "Identification of critical regions and candidate genes for cardiovascular malformations and cardiomyopathy associated with deletions of chromosome 1p36.." PLoS One. 2014 January 15; 9 (1): PLoS One. 2014;.
- Beck TF, Shchelochkov OA, Yu Z, Kim BJ, Hernández-García A, Zaveri HP, Bishop C, Overbeek PA, Stockton DW, Justice MJ, Scott DA. "Novel frem1-related mouse phenotypes and evidence of genetic interactions with gata4 and slit3.." PLoS One.. 2013 March 11; 8 (3): Published online.
- Kim BJ, Zaveri HP, Shchelochkov OA, Yu Z, Hernández-García A, Seymour ML, Oghalai JS, Pereira FA, Stockton DW, Justice MJ, Lee B, Scott DA. "An allelic series of mice reveals a role for RERE in the development of multiple organs affected in chromosome 1p36 deletions.." PLoS One.. 2013 February 25; 8 (2): Published online.
- Wat MJ, Beck TF, Hernández-García A, Yu Z, Veenma D, Garcia M, Holder AM, Wat JJ, Chen Y, Mohila CA, Lally KP, Dickinson M, Tibboel D, de Klein A, Lee B, Scott DA. "Mouse model reveals the role of SOX7 in the development of congenital diaphragmatic hernia associated with recurrent deletions of 8p23.1.." Hum Mol Genet.. 2012 September 15; 21 (18): 4115-25..
- Hernández-García A, Brosens E, Zaveri HP, de Jong EM, Yu Z, Namwanje M, Mayle A, Fernandes CJ, Lee B, Blazo M, Lalani SR, Tibboel D, de Klein A, Scott DA. "Contribution of LPP copy number and sequence changes to esophageal atresia, tracheoesophageal fistula, and VACTERL association.." Am J Med Genet A. 2012 July ; 158 (7): 1785-1787.
- Gonzales E, Julien B, Serrière-Lanneau V, Nicou A, Doignon I, Lagoudakis L, Garcin I, Azoulay D, Duclos-Vallée JC, Castaing D, Samuel D, Hernandez-Garcia A, Awad SS, Combettes L, Thevananther S, Tordjmann T. "ATP release after partial hepatectomy regulates liver regeneration in the rat.." J Hepatol. 2010 January ; 52 (1): 54-62.
- Carrillo-Ponce Mde L, Martínez-Ordaz VA, Velasco-Rodríguez VM, Hernández-García A, Hernández-Serrano MC, Sanmiguel F. "Serum lead, cadmium, and zinc levels in newborns with neural tube defects from a polluted zone in Mexico.." Reprod Toxicol. 2004 December ; 19 (2): 149-54.
- Hernandez-Garcia A, Vlachaki MT, Ittmann M, Chhikara M, Aguilar LK, Zhu X, Teh BS, Butler EB, Woo S, Thompson TC, Barrera-Saldana H, Aguilar-Cordova E. "Impact of preimmunization on adenoviral vector expression and toxicity in a subcutaneous mouse cancer model.." Mol Ther. 2002 September ; 6 (3): 342-348.
- Narasimhaswamy S Belaguli · Mao Zhang · Andres-Hernandez Garcia · David H Berger "PIAS1 is a GATA4 SUMO ligase that regulates GATA4-dependent intestinal promoters independent of SUMO ligase activity and GATA4 sumoylation.." PLOS ONE. 2012 April ; 7 (4): Published: Apri.
- A. Hernandez-Garcia · S. Thevananther · S.S. Awad "Identification of a Novel Epidermal Growth Factor Receptor (EGFR) Binding Activity of Cyclin D1 Promoter During HepG2 Cell Proliferation and in Human Hepatocellular Carcinoma." Journal of Surgical Research. 2009 February ; 151 (2): 188-189.
- Lisker R, Hernández A, Martínez-Lavin M, Mutchinick O, Armas C, Reyes P, Robles-Gil J. "Gerodermia osteodysplastica hereditaria: report of three affected brothers and literature review.." Am J Med Genet.. 1979 3 (4): 389-395.
- Sepúlveda J1, Gutiérrez F, Moreno M, Hernández A. "Peroxisomal proliferation induced by treatment with clofibrate in a patient with a peroxisomal disease.." Cell Biochem Biophys.. 2000 32 : 329-332.
- Gómez-Arroyo S1, Hernández-García A, Villalobos-Pietrini R. "Induction of sister-chromatid exchanges in Vicia faba by arsenic-contaminated drinking water.." Mutat Res.. 1988 July ; 208 (3): 219-224.
- Daryl A Scott, Andres Hernandez-Garcia, Mahshid S Azamian, Valerie K Jordan, Bum Jun Kim, Molly Starkovich, Jinglan Zhang, Lee-Jun Wong, Sandra A Darilek, Amy M Breman, Yaping Yang, James R Lupski, Amyn K Jiwani, Bibhuti Das, Seema R Lalani, et al "Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO." J Med Genet.. 2016 August 22; : Pubmed PMID: 27550220
- Jordan VK, Beck TF, Hernandez-Garcia A, Kundert PN, Kim BJ, Jhangiani SN, Gambin T, Starkovich M, Punetha J, Paine IS, Posey JE, Li AH, Muzny D, Hsu CW, Lashua AJ, Sun X, Fernandes CJ, Dickinson ME, Lally KP, Gibbs RA, Boerwinkle E, Lupski JR, Scott DA. "The Role of FREM2 and FRAS1 in the Development of Congenital Diaphragmatic Hernia.." Hum Mol Genet. 2028 June 15; 12 : 2064-2075. Pubmed PMID: 29618029
- Kim BJ, Zaveri HP, Jordan VK, Hernandez-Garcia A, Jacob DJ, Zamora DL, Yu W, Schwartz RJ, Scott DA "RERE deficiency leads to decreased expression of GATA4 and the development of ventricular septal defects.." Dis Model Mech.. 2018 August 28; 11 (9): 1-12. Pubmed PMID: 30061196
- Benjamin Cogne´, Sophie Ehresmann, Eliane Beauregard-Lacroix, Justine Rousseau, Thomas Besnard, Thomas Garcia, Slave´ Petrovski, Shiri Avni, Kirsty McWalter, Patrick R. Blackburn, Daryl A. Scott, Andres Hernandez-Garcia, et al.. "Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.." Am J Hum Genet.. 2019 March 7; 104 (3): 530-541. Pubmed PMID: 30827496
- Callaway DA1, Campbell IM2, Stover SR3, Hernandez-Garcia A3, Jhangiani SN3,4, Punetha J3, Paine IS3, Posey JE3, Muzny D3,4, Lally KP5, Lupski JR3,4,6, Shaw CA3, Fernandes CJ6, Scott DA3,7. "Prioritization of Candidate Genes for Congenital Diaphragmatic Hernia in a Critical Region on Chromosome 4p16 using a Machine-Learning Algorithm.." J Pediatr Genet.. 2018 December 7; 4 : 164-173. Pubmed PMID: 30430034
Projects
- The regulatory role of Sox7 in endocardial cushion morphogenesis, myocardial patterning and yolk sac vasculature development.
- Baylor College of Medicine (06/2010 - 09/2020)
- Houston Texas, USA
- SOX7 is located in a critical region for congenital heart defects (CHD) on chromosome 8p23.1 that is recurrently deleted in individuals with septal defects. SOX7 encodes a DNA binding transcription factor that is highly expressed in vascular endothelium and the endocardium during early embryonic development. To explore the role of SOX7 in cardiovascular development, we developed standard and conditional Sox7 knockout mice. Sox7 -/- embryos die around E11.5 with signs of heart failure, pericardial edema, and failure of vasculature remodeling. The same phenotype was observed when Sox7 was ablated in endothelial cells using a Tie2-Cre. This suggests that SOX7 plays a critical role in vasculogenesis. We also observed that Sox7-/- embryos had hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells and that one out of two Sox7 flox/flox;Tie2-Cre embryos that escaped early lethality had a ventricular septal defect. This led us to hypothesize that SOX7 might also be playing a critical role in the endocardium of the AV canal. To test this hypothesis, we performed explant studies in which we harvested the AV canals of E9.5 Sox7-/- embryos and their wild-type littermates, and cultured them on a collagen gel for 48 hours. By counting the number of migrating mesenchymal cells associated with each culture, we demonstrated that SOX7 deficiency leads to a severe reduction in endothelial-to-mesenchymal transition. Since SOX7 is a transcription factor, we assumed that it must function in the endocardium by regulating the expression of one or more genes that play a critical role in EMT. To identify these EMT-related genes in an unbiased manner, we performed RNA-seq on E9.5 hearts harvested from Sox7-/- embryos and their wild-type littermates. In these studies, we found that Wnt4 transcript levels were severely downregulated. Previous studies have shown that WNT4 is expressed in the endocardium, and promotes EMT by acting in a paracrine manner to increase the expression of BMP2 in the myocardium. Consistent with these findings, we found that Bmp2 transcript levels were also decreased in Sox7-/- embryonic hearts. Based on these findings, we conclude that SOX7 promotes EMT in the AV canal by modulating the expression of Wnt4, and that decreased expression of SOX7 contributes to the congenital heart defects seen in individuals with recurrent 8p23.1 microdeletions.
- Morphogenetic and Molecular Mechanisms Underlying SOX7/GATA4-Related Congenital Diaphragmatic Hernia
- Baylor College of Medicine (09/2016 - 09/2019)
- Houston Texas, USA
- Congenital diaphragmatic hernia occurs when the abdominal viscera—the liver, stomach, spleen and/or intestines—protrude into the thorax through a defect in the diaphragm. In 25-40% of cases, diaphragmatic hernias coexist with congenital heart defects (CHD). The addition of CHD doubles the mortality rate of diaphragmatic hernia from ~30% to nearly 60%. Many of the genes responsible for this life-threatening combination of birth defects have also been shown to cause isolated CHD. Our long-term goal is to identify these genes and determine the developmental and molecular mechanisms by which they cause CHD. Microdeletions of chromosome 8p23.1 are associated with a high penetrance of both CHD (94%) and diaphragmatic hernia (22%). Clinical data suggests that haploinsufficiency of two retinoic acid responsive transcription factors, GATA4 and SOX7, contribute to this high penetrance. Although a variety of cardiac defects have been documented in individuals with 8p23.1 deletions, atrioventricular (AV) septal defects are the most common. These defects have also been documented in Gata4+/- mice. Tissue specific deletion of Gata4 in the endocardium leads to a block in endothelial-to-mesenchymal transition (EMT) and a severe reduction in the number of mesenchymal cells within the endocardial cushions. These mesenchymal cells will ultimately form portions of the AV septum and its associated valves. Their deficiency leads to AV septal defects and valve anomalies. In contrast to GATA4, little is known about how SOX7-deficiency causes CHD. However, we have shown that SOX7 is expressed in the endocardium and that SOX7-deficient embryos also have hypoplastic endocardial cushions with decreased numbers of mesenchymal cells. Our preliminary data also suggest that ablation of Sox7 in the endocardium can cause septal defects. Previously published in vitro studies suggest that SOX7 can potentiate the expression of GATA4. This leads us to hypothesize that SOX7 promotes EMT by inducing the expression of GATA4 in endocardial cells. Data from in vitro and in vivo studies suggest that SOX7 may also promote EMT by stimulating the expression of the nuclear receptor NR2F2, whose deficiency also causes CHD and diaphragmatic hernias, or by potentiating Notch signaling. In this proposal, we will use our unique mouse resources—including standard and conditional Sox7 knockout mice generated in our laboratory—to understand the developmental and molecular mechanisms by which SOX7 deficiency contributes to the development of CHD. Our results will deepen our understanding of EMT regulation and will inform efforts to develop interventions to prevent or ameliorate the CHD associated with 8p23.1 deletions.
Memberships
- American Society of Human Genetics
- ASHG Member (10/2016)
Languages
Spanish
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