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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. 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.

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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.

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.

Accordingly, the non-RGPC-fated daughter cells need to break down their microadenoma 4mm 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 11prostata 50cc13 Enormous number of cell division events and subsequent delamination steps are required for the generation of hundreds of billions of neurons and other cell types in the brain.

Considering the remarkably microadenoma 4mm prevalence of congenital brain malformations, it is conceivable to hypothesize that a specific mechanism exists that protects against the consequences of sporadic delamination errors. 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 prostate volume calculator 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.

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.

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.

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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 ABHD4 is also essential for prenatal alcohol exposure-induced apoptosis providing insights into the mechanisms underlying cell death associated with fetal alcohol syndrome.

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 prostate volume calculator of N-cadherin ΔnCdh2-GFP into the lateral ventricles at embryonic day We exploited this conditional and sparse adherens junction injury protocol instead of the global loss-of-function IR lézer prosztatitis to restrict the effects in time and space to a selected population of Prostate volume calculator 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 prostate volume calculator 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. Data are shown as median line and interquartile range transparent band.

Scale bars: a—d, l—o: 50 μm, e—j: 25 μm. Source data are provided as a Source Data file. Full size image In order to investigate the fate of these pathologically detached RGPCs, we next tested whether cell death is also induced by prostate volume calculator 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 unaffected 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.

ABHD4-dependent developmental anoikis safeguards the embryonic brain

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.

Scale bars: a—d, l—s: 50 μm, e—j: 10 μm.

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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.

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

Notably, Abhd4 mRNA levels were below detection threshold in more committed neuronal progenitor prostate volume calculator populations and in adult cortical neuronal types 2425whereas Mellékvese kimerültség labor 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.

These experiments revealed that Abhd4 mRNA expression was remarkably abundant in prostate volume calculator germinative niches of the telencephalic and third brain ventricles, whereas it was absent in 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.

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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. Full size image Although RGPCs represent the majority of cells in prostate volume calculator 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. ABHD4 is sufficient to trigger apoptosis The previous experiments demonstrated strict spatial and temporal restriction of Abhd4 expression in RGPCs of the developing brain. RGPCs serve two major functions in the embryonic cerebral cortex: as progenitor cells 123 and by providing a scaffold for postmitotic neuroblast migration However, neither single-pulse bromodeoxyuridine-labeling of proliferating precursors Fig.

S6a—c revealed any quantitative differences prostate volume calculator wild-type and Abhd4-knockout mice.

Moreover, the laminar distribution of pyramidal cells, GABAergic interneurons and astrocytes was also unaltered in the adult neocortex of knockout animals Supplementary Fig.

Together, these results demonstrate that despite its high expression in RGPCs, ABHD4 is not necessary for the two major developmental functions of these progenitor cells. Graphs show box-and-whisker plots including minima, maxima and mean values with 2 × standard error, except p where median and lower, upper quartiles are presented with single values.

Scale bars: a—e, i—j: 50 μm, g—h: 20 μm, m, n: μm. Full size image These unexpected findings, together with the spatially and temporally restricted expression of Abhd4 in RGPCs, raise the possibility that this serine hydrolase has evolved to fulfill a hitherto undefined physiological function that is important in the cell biology of neurogenesis. Interestingly, phylogenetic analysis revealed that ABHD4 protein orthologues exhibit substantial homology that is especially high around the catalytic serine residue S in mouse 23 and the consensus nucleophile elbow sequence GXSXG, suggesting that the enzymatic function of ABHD4 is evolutionarily conserved Supplementary Fig.

Because Abhd4 expression is rapidly downregulated in delaminated daughter cells right after their fate-commitment Fig. To test this idea, we in utero electroporated either GFP alone, or wild-type Abhd4-GFP, or a catalytically inactive form of Abhd4-GFP in which the catalytic serine residue that is required for hydrolase activity was mutated to glycine, SG mutant at E Moreover, Abhd4-GFP-transfected cells lost the characteristic bipolar morphology of migrating neuroblasts and became shrunken, rounded, and had no leading processes Fig.

These morphological changes are hallmarks of imminent cell death. Data are shown as median line and interquartile range transparent band in the same prostate volume calculator.

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High-power images show bipolar migrating neurons e, gthat become rounded upon Abhd4-GFP-electroporation f. Graphs show bar plots with median ± interquartile range.

Scale bars: a—c: μm, e—g: 20 μm, i n: 50 μm. Full size image A shift in the balance of proapoptotic and pro-survival molecular mechanisms is critically important in anoikis-related cell fate decisions during transition of cells to a metastatic phenotype We reasoned that some daughter cells whose transfection coincided with their delamination should already express the essential pro-survival molecular toolset to escape from anoikis and prostate volume calculator be capable to balance the impact of exogenous Abhd4 over-expression by its direct downregulation.

Notably, we found that initially GFP expression in case of both of these constructs almost completely overlapped with the co-electroporated tdTomato marker 24 h after co-electroporation Supplementary Fig.

This observation suggests that only prostate volume calculator postmitotic neurons could undergo delayed migration by postnatal day 3 that could degrade their ABHD4-GFP fusion protein and indicate that ABHD4 activity is non-permissive for radial migration into the cortical plate.

To determine how powerfully ABHD4 drives cell death even without a native tissue context e. S10a—f, g and a concomitant rise in extra-mitochondrial cytochrome c levels, signs of early stage apoptosis Supplementary Fig.

S10e, f, h—j. Moreover, ABHD4 also elicited a large increase in the number of cleaved caspase 3-immunopositive cells exhibiting nuclear fragmentation and condensation, features of late stage apoptosis Supplementary Fig. In contrast, the adjacent untransfected cells remained unaffected Supplementary Fig. These results indicate that ABHD4 is capable of triggering an apoptotic program cell-autonomously even in cell types with a higher apoptotic threshold.

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ABHD4 is necessary for developmental anoikis It is well-established that cell type-specific consecutive waves of developmentally controlled programmed cell death delete a substantial proportion of neurons during cortical development 3435 Considering the proapoptotic activity of ABHD4, we therefore investigated the basal level of cell death in the developing neocortex. Notably, there was no difference in the density of dead cells in the subventricular and VZs of wild-type and Abhd4-knockout mice at embryonic day Developmentally controlled programmed cell death of glutamatergic cells peaks early postnatally 35 but we could detect no differences in cell death levels between the genotypes at postnatal day 3 either Supplementary Fig.

Graphs show box-and-whisker plots including minima, maxima, and mean values with 2 × standard error, except l where median and lower, upper quartiles are presented with single values. Scale bars: a—d: μm, f—k: 50 μm.

Full size image Importantly, physiologically controlled forms of programmed cell death or apoptosis induced by pathological insults do not prostate volume calculator share the same molecular mechanisms. Because our results have revealed that both adherens junction disruption-induced delamination and ectopic ABHD4 enzymatic activity in normally delaminating cells cause similar caspase-dependent cell death in the embryonic neocortex, we next tested the possibility that ABHD4 serves as a specific molecular link between pathological detachment and subsequent cell death.

To this end, ΔnCdh2-GFP was electroporated into the lateral ventricles of prostate volume calculator and littermate Abhd4-knockout embryos. Sparse adherens junction prostate volume calculator initiated a marked increase in the density of dead cells that was restricted to the VZ and SVZs see distribution analysis in Fig.

Importantly, this increase in cell death could be fully rescued by Abhd4 re-expression in Prostate volume calculator mice Fig. These findings prostate volume calculator that ABHD4 is not required for developmentally controlled programmed cell death, but it is essential for developmental anoikis, a unique form of cell death triggered by the damage of cadherin-based adherens junctions in the prenatal brain.