ABHD4-dependent developmental anoikis safeguards the embryonic brain | Nature Communications

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Neonatal brain damage 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.

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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.

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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.

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These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults. Download PDF Introduction In the developing brain, radial glia progenitor cells RGPCs spawn various cell types including intermediate progenitor cells, neurons, astrocytes, oligodendrocytes, and ependymal cells 1234.

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Following asymmetric cell division at the ventricular surface, the self-renewed RGPCs remain anchored to their neighbors via cadherin-based adherens junctions 56. This adhesion complex not only serves as a structural stabilizer, but it is also involved in important signaling mechanisms regulating cell cycle, proliferation, and differentiation, indicating that adherens junction assembly and disassembly are tightly coupled to cell fate decisions 789.

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Accordingly, the non-RGPC-fated daughter cells need to break down their adherens junctions to delaminate from the ventricular wall and to migrate to their functional destinations along the radial scaffold of RGPCs 69 Appropriately timed delamination is critically important for the mature daughter neuroblasts to follow their normal migratory route 6. In contrast, pathological detachment and abnormal dispersion of RGPCs, which retain their proliferative capacity at ectopic locations, represent a serious risk for brain malformations, such as focal cortical dysplasia or periventricular heterotopia, potentially predisposing to various forms of intellectual disabilities and neurological deficits 111213 Enormous number of cell division events and subsequent delamination steps are required for the generation of hundreds of billions of A prostatit súlyosbodott and other cell types in the brain.

Considering the remarkably low prevalence of congenital brain malformations, it is conceivable to hypothesize that a specific mechanism exists that protects against the consequences of sporadic delamination errors.

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Yet, how pathologically detached RGPCs are eliminated from the brain parenchyma and the related fundamental question of how fate-committed daughter cells become resistant to this defense mechanism both remain elusive. Along a similar line of reasoning, it is plausible to predict that such a protective mechanism should also be activated when pervasive injuries or teratogenic insults damage the adherens junctions in the prenatal brain.

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For example, germinal matrix hemorrhage, the most common neurological disease of preterm infants as well as microcephaly-associated environmental teratogens, such as the Zika virus and fetal alcohol exposure are all known to impair cell—cell adhesion in the germinative ventricular zone VZ leading to delamination and subsequent depletion of RGPC pools 151617 However, the molecular link between adherens junction damage and cell death induced by injury or by teratogenic insults remains unknown.

In the present study, we tested the hypothesis that a yet unidentified safeguarding mechanism determines distinct cell fate after normal delamination of daughter cells or pathological detachment of progenitor cells.

We demonstrate that adherens junction impairment induces aberrant RGPC delamination, ectopic accumulation, and caspase-mediated apoptosis in the subventricular zone SVZ and VZs, whereas caspase inhibition not only prevents the evoked cell death, but also rescues radial migration into the cortical plate.

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Moreover, abhydrolase domain containing 4 ABHD4a serine hydrolase with a yet undefined neurobiological function is identified as a necessary and sufficient mediator for the elimination of pathologically detached cells. Accordingly, healthy neuroblasts delaminating according to their normal developmental program switch off ABHD4 expression in parallel with their neurogenic commitment.

ABHD4 is not required for the canonical form of developmentally controlled programmed cell death in the embryonic neocortex indicating that its function is specifically associated with pathological insults. In agreement with this possibility, our findings elucidate that Prostate cancer review nature is also essential for prenatal alcohol exposure-induced apoptosis providing insights into the mechanisms underlying cell death associated with fetal testmozgás prosztatitis syndrome.

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Results Pathological RGPC detachment triggers developmental anoikis N-cadherin encoded by the Cdh2 gene is the major molecular component of the adherens junction belt along the ventricular wall in the developing mammalian brain 5. To interfere with cadherin-based cell-cell adhesions, we carried out in utero electroporation of a dominant-negative version of N-cadherin ΔnCdh2-GFP prostate cancer review nature the lateral ventricles at embryonic day We exploited this conditional and sparse adherens junction injury protocol instead of the global loss-of-function approaches to restrict prostate cancer review nature effects in time and prostate cancer review nature to a selected population of RGPCs and to avoid potential compensatory mechanisms that are more likely to come into play upon systems-level perturbations.

Confocal and STORM super-resolution microscopy revealed a striking specificity of this experimental manipulation as basal processes of electroporated RGPCs still reached the basal surface in ΔnCdh2-electroporated cortices Fig. Moreover, the morphology of the basal endfeet at the pial surface Fig. As a result of the adherens junction disruption, the detached RGPCs delaminated from the ventricular surface and accumulated in the SVZ. Most of these pathologically detached progenitor cells retained PAX6 transcription factor expression, a marker of RGPCs 19 even outside of the ventricular germinative niche Fig.

High-power fluorescent micrographs of the ventricular zone VZ show the adherens junction belt white arrowheads around the ventricle V. High-power images g, j demonstrate that the attachment of the basal endfeet of RGPCs to the pial surface is not affected directly by the disruption of cadherin-based adherens junctions at the ventricular surface.

Graphs show box-and-whisker plots including minima, maxima and median values, lower and upper quartiles with single values.

ABHD4-dependent developmental anoikis safeguards the embryonic brain | Nature Communications

Data are shown as median line and interquartile range transparent band. Scale bars: a—d, l—o: 50 μm, e—j: 25 μm.

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Source data are provided as a Source Data prostate cancer review nature. Full size image In order to investigate the fate of these pathologically detached RGPCs, we next tested whether cell death is also induced by adherens junction disruption.

In addition, administration of the pan-caspase inhibitor Z-VAD-FMK fully prevented the increase in cell death evoked by adherens junction disruption Fig. In contrast, basal cell death levels remained prostate cancer review nature demonstrating that pathological detachment specifically triggers a caspase-dependent apoptotic process Fig. These observations reinforce the idea that a specific cell death mechanism exists to eradicate pathologically detached progenitor cells in the developing neocortex, and this mechanism must be switched off in normally delaminating fate-comitted daughter cells to permit their migration to their functional destinations.

We termed this process developmental anoikis, because it conceptually resembles the specific form of apoptosis of epithelial cells induced by the loss of cell anchorage 20 Anoikis has primarily been implicated as a protective mechanism in tumor biology, and pathologically detached tumor cells need to develop resistance to anoikis to become able to invade distant organs during metastasis formation Graphs show box-and-whisker plots including minima, maxima, and median values, lower and upper quartiles with single values.

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Scale bars: a—d, l—s: 50 μm, e—j: 10 μm. Full size image Selective ABHD4 expression in RGPCs in the prenatal brain The previous experiments led us to hypothesize that specific molecular players have evolved to mediate delamination error-induced cell death. These signaling components must be present in anchorage-dependent RGPCs to protect them from pathological insults, but their expression should be downregulated in migrating healthy neuroblasts.

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Therefore, we searched public single-cell RNA-Seq databases, and identified abhydrolase domain containing 4 ABHD4an endocannabinoid-metabolizing enzyme 23 with a yet unknown in vivo function, as a potential molecular candidate.

Notably, Abhd4 mRNA levels were below detection threshold in more committed neuronal progenitor cell populations and in adult cortical neuronal types 2425whereas Abhd4 was found to be highly expressed in putative RGPC pools in both mouse and human embryonic cortical samples and cerebral organoids 26 The pattern of expression was very similar to the RGPC marker Pax6, but was complementary to that of Tbr1, a marker of differentiated neurons Supplementary Fig.

Moreover, a target-agnostic in vitro shRNA library screen in immortalized prostate epithelial cells suggested that downregulation of ABHD4 may potentially contribute to the resistance to anoikis To experimentally determine whether the expression pattern of ABHD4 matches with its potential functional role in the developing neocortex, we first performed in situ hybridization on wild-type and littermate Abhd4-knockout embryonic brains.

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These experiments revealed that Abhd4 mRNA expression was remarkably abundant in the germinative niches of the telencephalic and third brain ventricles, whereas it was absent prostate cancer review nature other regions and in control Abhd4-knockout embryonic brains Fig. This spatially restricted expression pattern was consistent throughout prenatal development Supplementary Fig. S5a—fbut Abhd4 expression markedly decreased postnatally in parallel with the reduced number of proliferating progenitors in the subventricular and subgranular zones Fig.

S5g—ireaching undetectable levels in adults. Immunoblotting with a specific antibody raised against a conserved disordered motif of the ABHD4 protein further confirmed the presence of this serine hydrolase enzyme in the developing neocortex of wild-type, but not of Abhd4-knockout control embryos Supplementary Fig.

High-power confocal imaging outlines the plasma membrane of ChR2-GFP-electroporated cells and delimits multi-color RNAscope analysis into single cells within the heterogeneous and densely packed cell layer of the ventricular zone.

The scatter plot shows data from individual cells normalized to the median value of the respective mRNA levels. Arrows point to the mitotic cleavage furrow between the dividing cells. Scale bars: a: μm, b—e, g—h, o—q: 50 μm, f: μm, i, j, l, m: 2 μm.

ABHD4-dependent developmental anoikis safeguards the embryonic brain

Full size image Although RGPCs represent the majority of cells in the germinative niches, it is important to note that fate-committed daughter cells that are undergoing delamination still populate the VZ, where the high cellular abundance renders cell-specific quantitative mRNA analysis very difficult.

To test the possibility that Abhd4 mRNA is preferentially segregated either into self-renewing RGPCs or daughter cells during cell division, we also measured Abhd4 expression by quantifying RNAscope in situ hybridization signal within mitotic cells visualized by PHH3-immunostaining.

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These findings together indicate that the temporal expression of Abhd4 in RGPCs is tightly controlled and its downregulation in fate-committed daughter cells starts rapidly after their delamination.