title: G-protein-coupled receptor signaling and neural tube closure defects.
abstract: Disruption of the normal mechanisms that mediate neural tube closure can result in neural tube defects (NTDs) with devastating consequences in affected patients. With the advent of next-generation sequencing, we are increasingly detecting mutations in multiple genes in NTD cases. However, our ability to determine which of these genes contribute to the malformation is limited by our understanding of the pathways controlling neural tube closure. G-protein-coupled receptors (GPCRs) comprise the largest family of transmembrane receptors in humans and have been historically favored as drug targets. Recent studies implicate several GPCRs and downstream signaling pathways in neural tube development and closure. In this review, we will discuss our current understanding of GPCR signaling pathways in pathogenesis of NTDs. Notable examples include the orphan primary cilia-localized GPCR, Gpr161 that regulates the basal suppression machinery of sonic hedgehog pathway by means of activation of cAMP-protein kinase A signaling in the neural tube, and protease-activated receptors that are activated by a local network of membrane-tethered proteases during neural tube closure involving the surface ectoderm. Understanding the role of these GPCR-regulated pathways in neural tube development and closure is essential toward identification of underlying genetic causes to prevent NTDs. Birth Defects Research 109:129-139, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Issei S
authors.initials: IS
authors.lastname: Shimada
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Saikat
authors.identifier: 0000-0003-4790-3090
authors.initials: S
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D054259:Neural Tube / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D009436:Neural Tube Defects / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054261:Neurulation / Q000235:genetics*; D038081:Organogenesis / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C000588604:GPR161 protein, human; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: G-protein-coupled receptor; Gpr161; cAMP; neural tube defect; primary cilia; protease-activated receptor; protein kinase A; sonic hedgehog