ABHD4-dependent developmental anoikis safeguards the embryonic brain

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.

Neurodevelopmental Disorders in Patients With Complex Phenotypes and Potential Complex Genetic Basis Involving Non-Coding Genes, and Double CNVs

“…Interestingly, chromosome 14 duplication encompassed ABHD4 , a gene recently shown to be involved in developmental anoikis, a mechanism of cell death in the prenatal brain preventing from survival of misplaced cells ( Laszlo et al, 2020 ). Indeed, ABHD4 is involved in N-acylethanolamine biosynthesis, including the endocannabinoid molecule anandamide which has various physiological functions such as the regulation of synaptic plasticity and apoptosis.…”

Selective measurement of NAPE-PLD activity via a PLA1/2-resistant fluorogenic N-acyl-phosphatidylethanolamine analog

“…ABHD4 acts as a PLA 1 and PLA 2 to convert NAPE to GP-NAE ( 19 ), which can be converted to NAE by GDE1 or GDE4 or other similar phosphodiesterases ( 6 , 15 , 16 ). Genetic deletion of A bhd4 in mice demonstrates that this NAE biosynthetic enzyme plays a critical role in developmental anoikis ( 47 ). Abhd4 deletion in mice does not significantly decrease their brain levels of AEA, OEA, PEA, or their precursor NAPEs, but does reduce levels of GP-NAEs ( 48 ).…”

Somatic junctions connect microglia and developing neurons

“…Also, microglia-specific interventions should be used to explore, whether the differentiation, migration or integration of progenitors / developing neurons is regulated through somatic junctions. Mitochondrial changes are involved in developmental apoptosis of neuronal progenitors (László et al, 2020), and these changes could also be sensed or even regulated by microglia, which can in turn eliminate unfit progenitors via inducing programmed cell death followed by phagocytosis. The NAD+:NADH ratio plays an important role in regulating stem cell-fate (Khacho and Slack, 2018), and we showed previously that microglia are able to regulate mitochondrial NADH-production at somatic junctions, in a P2Y12R-dependent manner (Cserép et al, 2020).…”