Control of cell behavior during cranial neural tube closure

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Abstract In vertebrates neural tube closure transforms the initially flat neuroepithelium into a closed, hollow tube that will give rise to the brain and spinal cord. Defects in this process are among the most common human birth defects, occurring in ~1:2000 pregnancies, and approximately half of these closure defects occur in the presumptive cranial region. However, we know very little about the cellular mechanisms that drive cranial closure, or how they are perturbed in mutants that fail at this process. Therefore, I propose to use a combination of imaging approaches coupled to quantitative cell wise computational analysis to characterize the cell behaviors, including apical constriction and cell proliferation, that drive cranial neural tube closure in the mouse model. Subsequently, I will examine how the cell behavioral profile is altered upon loss of cilia-mediated signaling thorough the Hedgehog pathway, which has been shown to lead to cranial closure defects. Finally, I will use transcriptomic approaches to parse the signaling pathways leading from cilia to cell behavior. Together, these experiments represent a significant advance in our understanding of the control of cell behaviors in cranial neural tube closure, a key concern in human development.