Eric Brooks, North Carolina State University

Eric Brooks, Ph.D., Assistant Professor of Quantitative Developmental Biology at North Carolina State

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Abstract

Failure in cranial neural tube closure is a common and lethal human structural birth defect. Cranial closure requires a dramatic inversion of tissue curvature of the initially outwardly convex neural folds, which drives elevation of the lateral borders of the tissue above the midline as a prerequisite for final closure. We show that this curvature change is initiated by the sustained apical constriction of a large population of thousands of cells located lateral to the midline, whereas midline cells remain static. This pattern of constriction stands in contrast to those observed in more posterior regions of the neural plate, where cell shape changes at the midline and/or more restricted lateral positions drive neural fold elevation. Further, we show that loss of function in the conserved intraflagellar transport A (IFT-A) complex required for cilia function and sonic hedgehog (Shh) signaling, disrupts patterned cell remodeling resulting in highly penetrant closure defects. These mutants exhibit a failure of apical constriction associated with defects in apical actomyosin organization in lateral cells, resulting in a failure of the cranial neural plate to convert from convex to concave. These defects are directly due to a dysregulated pattern of Shh signaling, as transgenic activation of the hedgehog signaling response throughout the midbrain neuroepithelium recapitulates the closure defects observed in IFT-A mutants. This anti-constrictive role of Shh signaling is likely to explain a large class of closure mutants with known or predicted roles in the spatial regulation of Hh signals within the tissue.

Join us on Monday, October 2 in Stephens Room (3503 Thomas Hall) and ZOOM for the Genetics and Genomics Seminar Series. Link: https://ncsu.zoom.us/j/91741454918?pwd=U0drVUpPdGJiSXVpcnVUZDNwaHVUZz09