The TFAP2A–IRF6–GRHL3 genetic pathway is conserved in neurulation

• Type of Material: Article
• Authors: Youssef A. Kousa, Michigan State University; Huiping Zhu, University of Texas Austin; Walid D. Fakhouri, University of Texas Houston; Yunping Lei, University of Texas Austin; Akira Kinoshita, Nagasaki University; Raeuf R. Roushagar, Michigan State University; Nicole K. Patel, Michigan State University; A. J. Agopian, University of Texas Houston; Elizabeth Leslie, Emory University; Brian C. Schutte, Michigan State University
• Language: English
• Date: 2019-03-15
• Publisher: Oxford University Press (OUP)
• Publication Version: Final Published Version
• Copyright Statement: Published by Oxford University Press 2019.
• License: Creative Commons Universal : Public Domain Dedication
• Final Published Version (URL): http://dx.doi.org/10.1093/hmg/ddz010
• Title of Journal or Parent Work: HUMAN MOLECULAR GENETICS
• Volume: 28
• Issue: 10
• Start Page: 1726
• End Page: 1737
• Grant/Funding Information: Michigan State University (to B.C.S.); National Institutes of Health (NIH) (DE13513 to B.C.S., F31DE022696 to Y.A.K. and B.C.S., DE025060 to E.J.L.); UT-Health School of Dentistry in Houston (to W.D.F., DE12728 and DE019843 to T.J.W.); and partial funding provided by CDC (5U01DD001033) and NIH (P01HD067244, GM072859 to G.M.S.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Keywords: neural tube defects; TFAP2A; GRHL3; neurulation; orofacial clefting syndrome; IRF6; genetic architecture
• Research Categories: Biology, Neuroscience; Biology, Genetics

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.