Progressive restriction in fate potential by neural progenitors during cerebral cortical development

Development ◽  
2000 ◽  
Vol 127 (13) ◽  
pp. 2863-2872 ◽  
Author(s):  
A.R. Desai ◽  
S.K. McConnell
Keyword(s):  
Progenitor Cells ◽  
Ventricular Zone ◽  
Cortical Development ◽  
Cortical Layer ◽  
Neural Progenitors ◽  
Environmental Cues ◽  
Middle Stage ◽  
Layer 2 ◽  
Layer 4 ◽  
Cortical Progenitor

During early stages of cerebral cortical development, progenitor cells in the ventricular zone are multipotent, producing neurons of many layers over successive cell divisions. The laminar fate of their progeny depends on environmental cues to which the cells respond prior to mitosis. By the end of neurogenesis, however, progenitors are lineally committed to producing upper-layer neurons. Here we assess the laminar fate potential of progenitors at a middle stage of cortical development. The progenitors of layer 4 neurons were first transplanted into older brains in which layer 2/3 was being generated. The transplanted neurons adopted a laminar fate appropriate for the new environment (layer 2/3), revealing that layer 4 progenitors are multipotent. Mid-stage progenitors were then transplanted into a younger environment, in which layer 6 neurons were being generated. The transplanted neurons bypassed layer 6, revealing that layer 4 progenitors have a restricted fate potential and are incompetent to respond to environmental cues that trigger layer 6 production. Instead, the transplanted cells migrated to layer 4, the position typical of their origin, and also to layer 5, a position appropriate for neither the host nor the donor environment. Because layer 5 neurogenesis is complete by the stage that progenitors were removed for transplantation, restrictions in laminar fate potential must lag behind the final production of a cortical layer. These results suggest that a combination of intrinsic and environmental cues controls the competence of cortical progenitor cells to produce neurons of different layers.

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Vol 116 (45) ◽  
pp. 22754-22763 ◽  
Author(s):  
Teresa G. Krieger ◽  
Carla M. Moran ◽  
Alberto Frangini ◽  
W. Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

scholarly journals The influence of cortical depth on neuronal responses in mouse visual cortex

2018 ◽  
Author(s):  
Philip O’Herron ◽  
John Woodward ◽  
Prakash Kara
Keyword(s):  
Visual Cortex ◽  
Neuronal Response ◽  
Superficial Layer ◽  
Cortical Layer ◽  
Contrast Imaging ◽  
Response Properties ◽  
Layer 2 ◽  
Layer 4 ◽  
Thalamic Projections ◽  
Mouse Visual Cortex

AbstractWith the advent of two-photon imaging as a tool for systems neuroscience, the mouse has become a preeminent model system for studying sensory processing. One notable difference that has been found however, between mice and traditional model species like cats and primates is the responsiveness of the cortex. In the primary visual cortex of cats and primates, nearly all neurons respond to simple visual stimuli like drifting gratings. In contrast, imaging studies in mice consistently find that only around half of the neurons respond to such stimuli. Here we show that visual responsiveness is strongly dependent on the cortical depth of neurons. Moving from superficial layer 2 down to layer 4, the percentage of responsive neurons increases dramatically, ultimately reaching levels similar to what is seen in other species. Over this span of cortical depth, neuronal response amplitude also increases and orientation selectivity moderately decreases. These depth dependent response properties may be explained by the distribution of thalamic inputs in mouse V1. Unlike in cats and primates where thalamic projections to the granular layer are constrained to layer 4, in mice they spread up into layer 2/3, qualitatively matching the distribution of response properties we see. These results show that the analysis of neural response properties must take into consideration not only the overall cortical lamina boundaries but also the depth of recorded neurons within each cortical layer. Furthermore, the inability to drive the majority of neurons in superficial layer 2/3 of mouse V1 with grating stimuli indicates that there may be fundamental differences in the role of V1 between rodents and other mammals.

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Author(s):  
Teresa G Krieger ◽  
Carla M Moran ◽  
Alberto Frangini ◽  
W Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation and organisation in human cerebral cortical development. They also exemplify novel quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

Isolated rat cortical progenitor cells are maintained in division in vitro by membrane-associated factors

Development ◽  
1994 ◽  
Vol 120 (4) ◽  
pp. 999-1008 ◽  
Author(s):  
S. Temple ◽  
A.A. Davis
Keyword(s):  
Cell Division ◽  
Progenitor Cells ◽  
Associated Factors ◽  
Progenitor Cell ◽  
Ventricular Zone ◽  
Single Cells ◽  
Cell Phenotype ◽  
Cortical Progenitor

Ventricular zone cells in the developing CNS undergo extensive cell division in vivo and under certain conditions in vitro. The culture conditions that promote cell division have been studied to determine the role that contact with cell membrane associated factors play in the proliferation of these cells. Progenitor cells have been taken from the ventricular zone of developing rat cerebral cortex and placed into microwells. Small clusters of these cells can generate large numbers of neurons and non-neuronal progeny. In contrast, single progenitor cells largely cease division, approximately 90% acquiring neuron-like characteristics by 1 day in vitro. DiI-labeled, single cells from embryonic day 14 cortex plated onto clusters of unmarked progenitor cells have a significantly higher probability (approximately 3-fold) of maintaining a progenitor cell phenotype than if plated onto the plastic substratum around 100 microns away from the clusters. Contact with purified astrocytes also promotes the progenitor cell phenotype, whereas contact with meningeal fibroblasts or balb3T3 cells promotes their differentiation. Membrane homogenates from cortical astrocytes stimulate significantly more incorporation of BrdU by E14 cortical progenitor cells than membrane homogenates from meningeal fibroblasts. These data indicate that the proliferation of rat cortical progenitor cells can be maintained by cell-type specific, membrane-associated factors.

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

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.

Presenilin-1 regulates neuronal differentiation during neurogenesis

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2593-2606 ◽  
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.

scholarly journals Induction of Recurrent Break Cluster Genes in Neural Progenitor Cells Differentiated from Embryonic Stem Cells In Culture

2019 ◽  
Author(s):  
Aseda Tena ◽  
Yuxiang Zhang ◽  
Nia Kyritsis ◽  
Anne Devorak ◽  
Jeffrey Zurita ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Progenitor Cells ◽  
Es Cells ◽  
Embryonic Stem ◽  
Neural Progenitors ◽  
Neural Genes ◽  
Genome Wide ◽  
Primary Mouse

ABSTRACTMild replication stress enhances appearance of dozens of robust recurrent genomic break clusters, termed RDCs, in cultured primary mouse neural stem and progenitor cells (NSPCs). Robust RDCs occur within genes (“RDC-genes”) that are long and have roles in neural cell communications and/or have been implicated in neuropsychiatric diseases or cancer. We sought to develop an in vitro approach to determine whether specific RDC formation is associated with neural development. For this purpose, we adapted a system to induce neural progenitor cell (NPC) development from mouse embryonic stem cell (ESC) lines deficient for XRCC4 plus p53, a genotype that enhances DNA double-strand break (DSB) persistence to enhance detection. We tested for RDCs by our genome wide DSB identification approach that captures DSBs genome-wide via their ability to join to specific genomic Cas9/sgRNA-generated bait DSBs. In XRCC4/p53-deficient ES cells, we detected 7 RDCs, which were in genes, with two RDCs being robust. In contrast, in NPCs derived from these ES cell lines, we detected 29 RDCs, a large fraction of which were robust and associated with long, transcribed neural genes that were also robust RDC-genes in primary NSPCs. These studies suggest that many RDCs present in NSPCs are developmentally influenced to occur in this cell type and indicate that induced development of NPCs from ES cells provides an approach to rapidly elucidate mechanistic aspects of NPC RDC formation.SIGNIFICANCE STATEMENTWe previously discovered a set of long neural genes susceptible to frequent DNA breaks in primary mouse brain progenitor cells. We termed these genes RDC-genes. RDC-gene breakage during brain development might alter neural gene function and contribute to neurological diseases and brain cancer. To provide an approach to characterize the unknown mechanism of neural RDC-gene breakage, we asked whether RDC-genes appear in neural progenitors differentiated from embryonic stem cells in culture. Indeed, robust RDC-genes appeared in neural progenitors differentiated in culture and many overlapped with robust RDC-genes in primary brain progenitors. These studies indicate that in vitro development of neural progenitors provides a model system for elucidating how RDC-genes are formed.

Pathologic Features of Dysplasia and Accompanying Alterations Observed in Surgical Specimens from Patients with Intractable Epilepsy

2004 ◽  
Vol 19 (3) ◽  
pp. 341-350 ◽  
Author(s):  
Akiyoshi Kakita ◽  
Shigeki Kameyama ◽  
Shintaro Hayashi ◽  
Hiroshi Masuda ◽  
Hitoshi Takahashi
Keyword(s):  
White Matter ◽  
Focal Cortical Dysplasia ◽  
Molecular Layer ◽  
Cortical Development ◽  
Neurofibrillary Tangle ◽  
Intractable Epilepsy ◽  
Clinical Findings ◽  
Cortical Layer ◽  
Pathologic Features ◽  
Cortical Dysplasias

Malformations caused by abnormalities of cortical development, or cortical dysplasias, were examined in surgical specimens from 108 patients with medically intractable epilepsy to determine the scope of histopathologic changes. The relevance of the clinical findings was also evaluated. Various types and degrees of dysplastic features were observed in various combinations, including architectural abnormalities, an increased number of neurons in the molecular layer and/or cortical layer II, neuronal clustering, an increased number of satellite oligodendrocytes, abnormal gyration, single and/or aggregates of heterotopic neurons in the white matter, and the appearance of cytologically abnormal cells, such as giant or dysmorphic neurons and balloon cells. In the temporal lobe specimens, microdysgenesis (corresponding to mild malformations caused by abnormalities of cortical development and type IA/B focal cortical dysplasias) was more frequently observed than Taylor-type focal cortical dysplasia (type IIA/B), whereas in the frontal lobe specimens, the frequency of occurrence of both types was even. The ages at seizure onset and surgery of patients with the latter type were significantly lower than those of patients with the former. On the other hand, prominent astrocytosis in the cortex and white matter was evident in all cases, and many corpora amylacea and neurofibrillary tangle—like inclusions were observed in a subset of cases. An ultrastructural investigation revealed dilatation of the postsynaptic dendritic spines and shafts in the cortex and features indicating the occurrence in the white matter of demyelination followed by remyelination. Thus, with regard to the epileptogenic lesions, although dysplastic changes constitute the pathogenetic basis, the overlapping subsequent degenerative processes involving synapses, dendrites, and axons might contribute to the development of epileptogenic processes. Astrocytes might also actively participate in the development of the pathogenesis of epilepsy. ( J Child Neurol 2005;20:341—350).

Lineage potential, plasticity and environmental reprogramming of epithelial stem/progenitor cells

2014 ◽  
Vol 42 (3) ◽  
pp. 637-644 ◽  
Author(s):  
Alessandro W. Amici ◽  
Fatai O. Onikoyi ◽  
Paola Bonfanti
Keyword(s):  
Stem Cells ◽  
Epithelial Cells ◽  
Cell Therapy ◽  
Hair Follicle ◽  
Progenitor Cells ◽  
Environmental Cues ◽  
Full Potential ◽  
Thymic Epithelium ◽  
Differentiated Cells ◽  
Stratified Epithelia

Recent evidence supports and reinforces the concept that environmental cues may reprogramme somatic cells and change their natural fate. In the present review, we concentrate on environmental reprogramming and fate potency of different epithelial cells. These include stratified epithelia, such as the epidermis, hair follicle, cornea and oesophagus, as well as the thymic epithelium, which stands alone among simple and stratified epithelia, and has been shown recently to contain stem cells. In addition, we briefly discuss the pancreas as an example of plasticity of intrinsic progenitors and even differentiated cells. Of relevance, examples of plasticity and fate change characterize pathologies such as oesophageal metaplasia, whose possible cell origin is still debated, but has important implications as a pre-neoplastic event. Although much work remains to be done in order to unravel the full potential and plasticity of epithelial cells, exploitation of this phenomenon has already entered the clinical arena, and might provide new avenues for future cell therapy of these tissues.

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