title: Shared molecular networks in orofacial and neural tube development.
abstract: Single genetic variants can affect multiple tissues during development. Thus it is possible that disruption of shared gene regulatory networks might underlie syndromic presentations. In this study, we explore this idea through examination of two critical developmental programs that control orofacial and neural tube development and identify shared regulatory factors and networks. Identification of these networks has the potential to yield additional candidate genes for poorly understood developmental disorders and assist in modeling and perhaps managing risk factors to prevent morbidly and mortality.
  
  
  
  We reviewed the literature to identify genes common between orofacial and neural tube defects and development. We then conducted a bioinformatic analysis to identify shared molecular targets and pathways in the development of these tissues. Finally, we examine publicly available RNA-Seq data to identify which of these genes are expressed in both tissues during development.
  
  
  
  We identify common regulatory factors in orofacial and neural tube development. Pathway enrichment analysis shows that folate, cancer and hedgehog signaling pathways are shared in neural tube and orofacial development. Developing neural tissues differentially express mouse exencephaly and cleft palate genes, whereas developing orofacial tissues were enriched for both clefting and neural tube defect genes.
  
  
  
  These data suggest that key developmental factors and pathways are shared between orofacial and neural tube defects. We conclude that it might be most beneficial to focus on common regulatory factors and pathways to better understand pathology and develop preventative measures for these birth defects. Birth Defects Research 109:169-179, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Pediatric Residency Program, Children's National Health System, Washington, DC.
authors.forename: Youssef A
authors.initials: YA
authors.lastname: Kousa
authors.affiliation: Department of Population Health and Reproduction, University of California, Davis, California.|Department of Clinical Pathology, College of Medicine, Mansoura University, Egypt.
authors.forename: Tamer A
authors.initials: TA
authors.lastname: Mansour
authors.affiliation: Department of Computer Science and Engineering, Computational Optimization and Innovation Laboratory, Michigan State University, East Lansing, Michigan.
authors.forename: Haitham
authors.initials: H
authors.lastname: Seada
authors.affiliation: Department of Modern Science, Islamic Azad University-Tehran Medical Branch, Tehran, Iran.
authors.forename: Samaneh
authors.initials: S
authors.lastname: Matoo
authors.affiliation: Department of Microbiology and Molecular Genetics and the Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Schutte
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057225:Data Mining; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D054259:Neural Tube / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D009436:Neural Tube Defects / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054261:Neurulation / Q000235:genetics*; D038081:Organogenesis / Q000235:genetics; D015398:Signal Transduction; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C473143:GRHL3 protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; C493673:TFAP2A protein, human; D050656:Transcription Factor AP-2; D014157:Transcription Factors
keywords: CLP; GRHL3; IRF6; TFAP2A; Van der Woude Syndrome; cleft lip; cleft lip and palate; cleft palate; embryonic development; human genetics; mouse models; neural tube defects; orofacial clefts; popliteal pterygium syndrome; spina bifida