Neural tube closure: a biological and computational approach to understanding the developmental and folate-protective mechanisms.

This research will to pursue an integrated approach to spinal and cranial neurulation in the mouse, using available NTD models and related genetic tools. Our first goal is to perform an experimental analysis of developmental mechanisms underlying spinal neural tube closure, with the aim of integrating existing ideas on long-range regulation of morphogenesis by BMPs, local matrix-mediated tissue interactions, and intracellular cytoskeleton-mediated cell shaping. In particular, we will use the Zic 2Ku mutant in which spinal neuroepithelial bending fails leading to spina bifida. A second goal is to determine the mechanisms underlying prevention of NTDs by folic acid and the risk imposed by folate deficiency. We will investigate the cause of cranial NTDs in splotch (Pax3) mice, and determine how folate status interacts with these processes and with other cellular functions essential for neurulation. Our third goal is to link the biological mechanisms with their mechanical consequences. We will construct a cell-based computational model of the mechanics of neuroepithelial bending, using inputs including cell and tissue geometry and tissue mechanical properties. The model will test hypotheses on the mechanical sufficiency of the proposed biological mechanisms for morphogenesis, initially focussing on the forces required for neural plate bending.