Journal article
The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation
Human molecular genetics, Vol.28(10), pp.1726-1737
05/15/2019
DOI: 10.1093/hmg/ddz010
PMCID: PMC6494790
PMID: 30689861
Abstract
Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.
Details
- Title: Subtitle
- The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation
- Creators
- Youssef A Kousa - Center for Neuroscience Research, The Childrens Research Institute, Washington, DC, USAHuiping Zhu - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USAWalid D Fakhouri - Department of Diagnostic & Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, USAYunping Lei - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USAAkira Kinoshita - Department of Human Genetics, Nagasaki University, Nagasaki, JapanRaeuf R Roushangar - Departments of Biochemistry and Molecular BiologyNicole K Patel - Microbiology and Molecular GeneticsA J Agopian - Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USAWei Yang - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USAElizabeth J Leslie - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USATamara D Busch - Departments of PediatricsTamer A Mansour - Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USAXiao Li - Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USAArianna L Smith - Genetics PhD ProgramEdward B Li - Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USADhruv B Sharma - Center for Statistical Training & Consulting, Michigan State University, East Lansing, MI, USATrevor J Williams - Department of Craniofacial Biology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USAYang Chai - Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USABrad A Amendt - Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USAEric C Liao - Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USALaura E Mitchell - Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USAAlexander G Bassuk - Departments of PediatricsSimon Gregory - Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USAAllison Ashley-Koch - Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USAGary M Shaw - Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USARichard H Finnell - Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USABrian C Schutte - Pediatrics and Human Development
- Resource Type
- Journal article
- Publication Details
- Human molecular genetics, Vol.28(10), pp.1726-1737
- DOI
- 10.1093/hmg/ddz010
- PMID
- 30689861
- PMCID
- PMC6494790
- NLM abbreviation
- Hum Mol Genet
- ISSN
- 0964-6906
- eISSN
- 1460-2083
- Publisher
- England
- Grant note
- R15 GM122030 / NIGMS NIH HHS
- Language
- English
- Date published
- 05/15/2019
- Academic Unit
- Neurology; Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Craniofacial Anomalies Research Center; Neurology (Pediatrics); Dental Research
- Record Identifier
- 9984025422202771
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