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Hum Mol Genet. 2019 Jan 25. doi: 10.1093/hmg/ddz010. [Epub ahead of print]

The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation.

Author information

1
Departments of Biochemistry and Molecular Biology.
2
Division of Neurology, Childrens National Health System.
3
Center for Neuroscience Research, The Childrens Research Institute, Washington, DC, USA.
4
Dell Pediatric Research Institute, Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA.
5
Department of Diagnostic & Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, USA.
6
Department of Human Genetics, Nagasaki University, Nagasaki, Japan.
7
Microbiology and Molecular Genetics.
8
Human Genetics Center, Division of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston, TX, USA.
9
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
10
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
11
Departments of Pediatrics.
12
Genetics PhD Program.
13
Department of Clinical Pathology, School of Medicine, University of Mansoura, Mansoura, Egypt.
14
Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA.
15
Anatomy and Cell Biology, University of Iowa, Iowa City, IA, USA.
16
Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
17
Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA.
18
Center for Statistical Training & Consulting, Michigan State University, East Lansing, MI, USA.
19
Department of Craniofacial Biology, University of Colorado Denver at Anschutz Medical Campus, Aurora, CO, USA.
20
Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
21
Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
22
Pediatrics and Human Development.

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.

PMID:
30689861
PMCID:
PMC6494790
[Available on 2020-05-15]
DOI:
10.1093/hmg/ddz010

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