Abstract
A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. After mitosis, fate-committed daughter cells delaminate from this germinative zone. Considering the high number of cell divisions and delaminations taking place during embryonic development, brain malformations caused by ectopic proliferation of misplaced progenitor cells are relatively rare. Here, we report that a process we term developmental anoikis distinguishes the pathological detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. We identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of pathologically 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.
Highlights
A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain
We demonstrate that adherens junction impairment induces aberrant radial glia progenitor cells (RGPCs) delamination, ectopic accumulation, and caspase-mediated apoptosis in the subventricular zone (SVZ) and VZs, whereas caspase inhibition prevents the evoked cell death, and rescues radial migration into the cortical plate
To interfere with cadherin-based cell-cell adhesions, we carried out in utero electroporation of a dominant-negative version of N-cadherin (ΔnCdh2-GFP) into the lateral ventricles at embryonic day 14.5 (E14.5). We exploited this conditional and sparse adherens junction injury protocol instead of the global loss-of-function approaches to restrict the effects in time and space to a selected population of RGPCs and to avoid potential compensatory mechanisms that are more likely to come into play upon systemslevel perturbations
Summary
A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. ABHD4 is not required for the canonical form of developmentally controlled programmed cell death in the embryonic neocortex indicating that its function is associated with pathological insults.
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