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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.
ABHD4-dependent developmental anoikis safeguards the embryonic brain | Nature Communications
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.
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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.
Following asymmetric cell division at the nyitott térd sérülések 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 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 neurons 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.
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 stage 4 metastatic prostate cancer forum 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, fáj a jobb vállízület 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.
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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 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 version 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 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 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 stage 4 metastatic prostate cancer forum ventricular germinative niche Fig. High-power fluorescent micrographs of the csípőízületek betegségei csípőbetegség tünetei 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.
Az beteg bevonásával végzett randomizált, kettős-vak intervenciós vizsgálat elsődleges végpontjai a radiológiai progressziómentes túlélés rPFS, Radiographic Progression-Free Survival és a teljes túlélés OS, overall survival voltak. Az Erleadát A másik vizsgálati karon a betegek az ADT mellett placebót kaptak, azonos adagolási gyakorisággal. A multicentrikus vizsgálatot vizsgálóhelyen végezték, többek között Budapest, Győr, Pécs és Sopron onkológiai központjainak bevonásával.
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.
All rights reserved. Ginger February 16, Julie L. Ginger, the rhizome of Zingiber officinale Roscoe, is best known for its role as a flavoring agent for food in Asian and Indian recipes.
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 adherens junction disruption.