title: Axons get ahead: Insights into axon guidance and congenital cranial dysinnervation disorders.
abstract: Cranial nerves innervate head muscles in a well-characterized and highly conserved pattern. Identification of genes responsible for human congenital disorders of these nerves, combined with the analysis of their role in axonal development in animal models, has advanced understanding of how neuromuscular connectivity is established. Here, we focus on the ocular motor system, as an instructive example of the success of this approach in unravelling the aetiology of human strabismus. The discovery that ocular motility disorders can arise from mutations in transcription factors, including HoxA1, HoxB1, MafB, Phox2A, and Sall4, has revealed gene regulatory networks that pattern the brainstem and/or govern the differentiation of cranial motor neurons. Mutations in genes involved in axon growth and guidance disrupt specific stages of the extension and pathfinding of ocular motor nerves, and have been implicated in human strabismus. These genes encompass varied classes of molecule, from receptor complexes to dynamic effectors to cytoskeletal components, including Robo3/Rig1, Alpha2-chimaerin, Kif21A, TUBB2, and TUBB3. A current challenge is to understand the protein regulatory networks that link the cell surface to the cytoskeleton and to dissect the co-ordinated signalling cascades and motile responses that underpin axonal navigation. Here we review recent insights derived from basic and clinical science approaches, to show how, by capitalising on the strengths of each, a more complete picture of the aetiology of human congenital cranial dysinnervation disorders can be achieved. This elucidation of these principles illustrates the success of clinical genetic studies working in tandem with molecular and cellular models to enhance our understanding of human disease. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 861-875, 2017.
authors.affiliation: Wellcome Wolfson Centre for Medical Research, University of Exeter Medical School, Wellcome-Wolfson Centre for Medical Research, Exeter, EX2 5DW, United Kingdom.
authors.forename: John K
authors.identifier: 0000-0001-9436-1357
authors.initials: JK
authors.lastname: Chilton
authors.affiliation: School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG.
authors.forename: Sarah
authors.initials: S
authors.lastname: Guthrie
mesh_terms: D000818:Animals; D000071437:Axon Guidance / Q000502:physiology*; D001369:Axons / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology*; D003391:Cranial Nerves / Q000503:physiopathology*; D006801:Humans; D009046:Motor Neurons / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: Duane retraction syndrome; axon guidance; congenital cranial dysinnervation disorders; motor neurons; ocular motor system