ABHD4-dependent developmental anoikis protects the prenatal brain from pathological insults

In light of the astronomical number of cell divisions taking place in restricted neurogenic niches, brain malformations caused by ectopic proliferation of misplaced progenitor cells are surprisingly rare. Here, we show that a process we term developmental anoikis distinguishes the abnormal detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. By using gain-of-function, loss-of-function, and rescue manipulations together with correlated confocal and super-resolution imaging, we identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of abnormally detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults.