Sec24b selectively sorts Vangl2 to regulate planar cell polarity during neural tube closure

Abstract

Craniorachischisis is a rare but severe birth defect that results in a completely open neural tube. Mouse mutants in planar cell polarity (PCP) signaling components have deficits in the morphological movements of convergent extension (CE) that result in craniorachischisis. Using a forward-genetic screen in mice, we have identified Sec24b, a cargo-sorting member of the core complex of the COPII endoplasmic reticulum (ER)-Golgi transport vesicle, as critical for neural tube closure. Sec24bY613 mutants exhibit craniorachischisis, deficiencies in CE, and other PCP-related phenotypes. Vangl2, a key component of the PCP-signaling pathway critical for CE, is selectively sorted into COPII vesicles by Sec24b. Moreover, Sec24bY613 genetically interacts with a loss-of-function Vangl2 allele (Vangl2LP) causing a marked increase in the prevalence of spina bifida. Interestingly, the Vangl2 looptail point mutants D255E and S464N, known to cause defects in CE, fail to sort into COPII vesicles and are trapped in the ER. Thus, during COPII vesicle formation, Sec24b exhibits cargo specificity for a core PCP component, Vangl2, the proper ER to Golgi transport of which is essential for the establishment of PCP, convergent extension, and closure of the neural tube.