Increased 5-hydroxymethylation levels in the sub ventricular zone of the Alzheimer's brain

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

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Development of the Neuro-Immune-Vascular Plexus in the Ventricular Zone of the Prenatal Rat Neocortex

Cerebral Cortex ◽

10.1093/cercor/bhaa351 ◽

2020 ◽

Author(s):

Elisa Penna ◽

Jon M Mangum ◽

Hunter Shepherd ◽

Veronica Martínez-Cerdeño ◽

Stephen C Noctor

Keyword(s):

Cerebral Cortex ◽

Ventricular Zone ◽

Cortical Development ◽

Neural Precursor Cells ◽

Neurodevelopmental Outcomes ◽

Vascular Plexus ◽

Functional Roles ◽

Rat Neocortex ◽

Cell Processes ◽

Temporal And Spatial

Abstract Microglial cells make extensive contacts with neural precursor cells (NPCs) and affiliate with vasculature in the developing cerebral cortex. But how vasculature contributes to cortical histogenesis is not yet fully understood. To better understand functional roles of developing vasculature in the embryonic rat cerebral cortex, we investigated the temporal and spatial relationships between vessels, microglia, and NPCs in the ventricular zone. Our results show that endothelial cells in developing cortical vessels extend numerous fine processes that directly contact mitotic NPCs and microglia; that these processes protrude from vessel walls and are distinct from tip cell processes; and that microglia, NPCs, and vessels are highly interconnected near the ventricle. These findings demonstrate the complex environment in which NPCs are embedded in cortical proliferative zones and suggest that developing vasculature represents a source of signaling with the potential to broadly influence cortical development. In summary, cortical histogenesis arises from the interplay among NPCs, microglia, and developing vasculature. Thus, factors that impinge on any single component have the potential to change the trajectory of cortical development and increase susceptibility for altered neurodevelopmental outcomes.

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Altered offspring neurodevelopment in an arginine vasopressin preeclampsia model

Translational Psychiatry ◽

10.1038/s41398-021-01205-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Serena Banu Gumusoglu ◽

Akanksha Sri Satya Chilukuri ◽

Benjamin Wen Qing Hing ◽

Sabrina Marie Scroggins ◽

Sreelekha Kundu ◽

...

Keyword(s):

Arginine Vasopressin ◽

Ventricular Zone ◽

Vessel Diameter ◽

Female Offspring ◽

Cell Number ◽

Differentially Expressed ◽

Adult Males ◽

Social Approach ◽

Caudate Putamen ◽

Underlying Mechanisms

AbstractPreeclampsia is a severe gestational hypertensive condition linked to child neuropsychiatric disorders, although underlying mechanisms are unclear. We used a recently developed, clinically relevant animal model of preeclampsia to assess offspring. C57BL/6J mouse dams were chronically infused with arginine vasopressin (AVP) or saline (24 ng/h) throughout pregnancy. Adult offspring were behaviorally tested (Y-maze, open field, rotarod, social approach, and elevated plus maze). Offspring brain was assessed histologically and by RNA sequencing. Preeclampsia-exposed adult males exhibited increased anxiety-like behavior and social approach while adult females exhibited impaired procedural learning. Adult AVP-exposed males had reduced total neocortical volume. Adult AVP-exposed females had increased caudate–putamen volume, increased caudate–putamen cell number, and decreased excitatory synapse density in hippocampal dentate gyrus (DG), CA1, and CA3. At postnatal day 7 (P7), AVP-exposed male and female offspring both had smaller neocortex. At P7, AVP-exposed males also had smaller caudate–putamen volume, while females had increased caudate–putamen volume relative to neocortical size. Similar to P7, E18 AVP-exposed offspring had smaller dorsal forebrain, mainly in reduced intermediate, subventricular, and ventricular zone volume, particularly in males. Decreased volume was not accounted for by cell size or cerebrovascular vessel diameter changes. E18 cortical RNAseq revealed 49 differentially-expressed genes in male AVP-exposed offspring, over-representing cytoplasmic translation processes. In females, 31 genes were differentially-expressed, over-representing collagen-related and epithelial regulation pathways. Gene expression changes in E18 AVP-exposed placenta indicated potential underlying mechanisms. Deficits in behavior and forebrain development in this AVP-based preeclampsia model were distinctly different in males and females, implicating different neurobiological bases.

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The induction of multiple cell cycle events precedes target-related neuronal death

Development ◽

10.1242/dev.121.8.2385 ◽

1995 ◽

Vol 121 (8) ◽

pp. 2385-2395 ◽

Cited By ~ 1

Author(s):

K. Herrup ◽

J.C. Busser

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Purkinje Cell ◽

Inferior Olive ◽

Granule Cells ◽

Cerebellar Granule Cells ◽

Ventricular Zone ◽

Nuclear Antigen ◽

Electron Microscopic ◽

Related Cell

Unexpected nerve cell death has been reported in several experimental situations where neurons have been forced to re-enter the cell cycle after leaving the ventricular zone and entering the G0, non-mitotic stage. To determine whether an association between cell death and unscheduled cell cycling might be found in conjunction with any naturally occurring developmental events, we have examined target-related cell death in two neuronal populations, the granule cells of the cerebellar cortex and the neurons of the inferior olive. Both of these cell populations have a demonstrated developmental dependency on their synaptic target, the cerebellar Purkinje cell. Two mouse neurological mutants, staggerer (sg/sg) and lurcher (+/Lc), are characterized by intrinsic Purkinje cell deficiencies and, in both mutants, substantial numbers of cerebellar granule cells and inferior olive neurons die due to the absence of trophic support from their main postsynaptic target. We report here that the levels of three independent cell cycle markers--cyclin D, proliferating cell nuclear antigen and bromodeoxyuridine incorporation--are elevated in the granule cells before they die. Although lurcher Purkinje cells die during a similar developmental period, no compelling evidence for any cell cycle involvement in this instance of pre-programmed cell death could be found. While application of the TUNEL technique (in situ terminal transferase end-labeling of fragmented DNA) failed to label dying granule cells in either mutant, light and electron microscopic observations are consistent with the interpretation that the death of these cells is apoptotic in nature. Together, the data indicate that target-related cell death in the developing central nervous system is associated with a mechanism of cell death that involves an apparent loss of cell cycle control.

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Presenilin-1 regulates neuronal differentiation during neurogenesis

Development ◽

10.1242/dev.127.12.2593 ◽

2000 ◽

Vol 127 (12) ◽

pp. 2593-2606 ◽

Cited By ~ 1

Author(s):

M. Handler ◽

X. Yang ◽

J. Shen

Keyword(s):

Cell Death ◽

Progenitor Cells ◽

Neuronal Differentiation ◽

Cell Fate ◽

Neural Progenitor Cells ◽

Apoptotic Cell ◽

Ventricular Zone ◽

Neural Progenitor ◽

Apoptotic Cell Death ◽

Presenilin 1

Mutations in Presenilin-1 (PS1) are a major cause of familial Alzheimer's disease. Our previous studies showed that PS1 is required for murine neural development. Here we report that lack of PS1 leads to premature differentiation of neural progenitor cells, indicating a role for PS1 in a cell fate decision between postmitotic neurons and neural progenitor cells. Neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(−/−) mice, suggesting that the reduction in the neural progenitor cells observed in the PS1(−/−) brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In addition, the premature neuronal differentiation in the PS1(−/−) brain is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere. In the ventricular zone of PS1(−/−) mice, expression of the Notch1 downstream effector gene Hes5 is reduced and expression of the Notch1 ligand Dll1 is elevated, whereas expression of Notch1 is unchanged. The level of Dll1 transcripts is also increased in the presomitic mesoderm of PS1(−/−) embryos, while the level of Notch1 transcripts is unchanged, in contrast to a previous report (Wong et al., 1997, Nature 387, 288–292). These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis.

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Diminished ventral oligodendrocyte precursor generation results in the subsequent over-production of dorsal oligodendrocyte precursors of aberrant morphology and function

10.1101/2020.03.09.983908 ◽

2020 ◽

Author(s):

Lev Starikov ◽

Andreas H. Kottmann

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Ventricular Zone ◽

Normal Numbers ◽

Spinal Cord Development ◽

Oligodendrocyte Precursor ◽

And Function ◽

Sod1 Mouse ◽

Lateral Sclerosis ◽

Ventral Spinal Cord

AbstractOligodendrocyte precursor cells (OPCs) arise sequentially first from a ventral and then from a dorsal precursor domain at the end of neurogenesis during spinal cord development. Whether the sequential production of OPCs is of physiological significance has not been examined. Here we show that ablating Shh signaling from nascent ventricular zone derivatives and partially from the floor plate results in a severe diminishment of ventral derived OPCs but normal numbers of motor neurons in the postnatal spinal cord. In the absence of ventral vOPCs, dorsal dOPCs populate the entire spinal cord resulting in an increased OPC density in the ventral horns. These OPCs take on an altered morphology, do not participate in the removal of excitatory vGlut1 synapses from injured motor neurons, and exhibit morphological features similar to those found in the vicinity of motor neurons in the SOD1 mouse model of Amyotrophic Lateral Sclerosis (ALS). Our data indicates that vOPCs prevent dOPCs from invading ventral spinal cord laminae and suggests that vOPCs have a unique ability to communicate with injured motor neurons.

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Ventricular Zone Disruption in Human Neonates With Intraventricular Hemorrhage

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlx077 ◽

2017 ◽

Vol 76 (12) ◽

pp. 1064-1064

Keyword(s):

Intraventricular Hemorrhage ◽

Ventricular Zone ◽

Human Neonates

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Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex

Developmental Neuroscience ◽

10.1159/000369092 ◽

2015 ◽

Vol 37 (2) ◽

pp. 131-141 ◽

Cited By ~ 7

Author(s):

Shuhong Qiao ◽

Ramin Homayouni

Keyword(s):

Brain Development ◽

Cortical Neurons ◽

Ventricular Zone ◽

Physiological Role ◽

Immunohistochemical Analysis ◽

Superficial Layer ◽

Tumor Formation ◽

Intermediate Zone ◽

Cortical Plate ◽

Integrin Signaling

Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase-activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP-knockdown (KD) mouse model created by retroviral insertion of a LacZ-encoding gene-trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunohistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. Bromodeoxyuridine birth dating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II-IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP-KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition from multipolar to bipolar morphology in migrating postmitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of the cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP-KD brains. We found that Dab2IP-KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a subpopulation of later-born (layers II-IV) neurons, likely through the regulation of Rap1 and integrin signaling.

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