Cellular mechanisms underlying the morphogenetic biomechanics of mammalian neural tube closure (360G-Wellcome-211112_Z_18_A)
Primary neurulation is a biomechanical process whereby the flat neural plate folds into a closed neural tube (NT). Closure initiates at the hindbrain/cervical boundary and "zippers" bi-directionally to form the cephalic and spinal NT. Failure of NT closure results in defects including spina bifida, which continue to affect 1:1,000 pregnancies. Despite advances in delineating its genetic control, we lack an integrated understanding of neurulation as a biomechanical morphogenetic process. To this end I have combined mouse posterior neuropore (PNP) live-imaging, laser ablation, and novel strain-mapping workflows to describe the tissue-level biomechanics of spinal closure. These revealed that the PNP is biomechanically coupled by a far-reaching actomyosin network, identified teratogenic/genetic models in which altered PNP biomechanics predict spina bifida, and identified a novel closure-initiation point ("Closure 5") which forms at the embryo’s caudal extreme. We now propose to determine: Are mechanical forces which promote and oppose NT closure balanced through actomyosin-dependent contractility overcoming tissue rigidity, up to a failure threshold? Do biomechanical differences between spinal and cephalic closure account for the latter’s apparent predisposition to failure? Does Closure 5 formation critically facilitate completion of spinal neural tube closure in humans and mice, and how is its morphogenesis regulated?
£25,000 30 Sep 2018