Lin28 promotes the proliferative capacity of neural progenitor cells in brain development

ABSTRACT The mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV infection to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here, we show that HCMV infection of NPCs results in loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 downregulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection. IMPORTANCE Human cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss, and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.

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Human Cytomegalovirus Immediate-Early 1 Protein Causes Loss of SOX2 from Neural Progenitor Cells by Trapping Unphosphorylated STAT3 in the Nucleus

10.1101/308171 ◽

2018 ◽

Author(s):

Cong-Cong Wu ◽

Xuan Jiang ◽

Xian-Zhang Wang ◽

Xi-Juan Liu ◽

Xiao-Jun Li ◽

...

Keyword(s):

Transcription Factor ◽

Brain Development ◽

Progenitor Cells ◽

Human Cytomegalovirus ◽

Neural Progenitor Cells ◽

Hcmv Infection ◽

Neural Progenitor ◽

Immediate Early ◽

Cell Protein ◽

Sox2 Expression

ABSTRACTThe mechanisms underlying neurodevelopmental damage caused by virus infections remain poorly defined. Congenital human cytomegalovirus (HCMV) infection is the leading cause of fetal brain development disorders. Previous work has linked HCMV to perturbations of neural cell fate, including premature differentiation of neural progenitor cells (NPCs). Here we show that HCMV infection of NPCs results in the loss of the SOX2 protein, a key pluripotency-associated transcription factor. SOX2 depletion maps to the HCMV major immediate-early (IE) transcription unit and is individually mediated by the IE1 and IE2 proteins. IE1 causes SOX2 down-regulation by promoting the nuclear accumulation and inhibiting the phosphorylation of STAT3, a transcriptional activator of SOX2 expression. Deranged signaling resulting in depletion of a critical stem cell protein is an unanticipated mechanism by which the viral major IE proteins may contribute to brain development disorders caused by congenital HCMV infection.IMPORTANCEHuman cytomegalovirus (HCMV) infections are a leading cause of brain damage, hearing loss and other neurological disabilities in children. We report that the HCMV proteins known as IE1 and IE2 target expression of human SOX2, a central pluripotency-associated transcription factor that governs neural progenitor cell (NPC) fate and is required for normal brain development. Both during HCMV infection and when expressed alone, IE1 causes the loss of SOX2 from NPCs. IE1 mediates SOX2 depletion by targeting STAT3, a critical upstream regulator of SOX2 expression. Our findings reveal an unanticipated mechanism by which a common virus may cause damage to the developing nervous system and suggest novel targets for medical intervention.

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Selective Lengthening of the Cell Cycle in the Neurogenic Subpopulation of Neural Progenitor Cells during Mouse Brain Development

Journal of Neuroscience ◽

10.1523/jneurosci.0778-05.2005 ◽

2005 ◽

Vol 25 (28) ◽

pp. 6533-6538 ◽

Cited By ~ 235

Author(s):

F. Calegari

Keyword(s):

Cell Cycle ◽

Brain Development ◽

Progenitor Cells ◽

Mouse Brain ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Mouse Brain Development

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Timing the spinal cord development with neural progenitor cells losing their proliferative capacity: a theoretical analysis

Neural Development ◽

10.1186/s13064-019-0131-3 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 1

Author(s):

Manon Azaïs ◽

Eric Agius ◽

Stéphane Blanco ◽

Angie Molina ◽

Fabienne Pituello ◽

...

Keyword(s):

Spinal Cord ◽

Theoretical Analysis ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Proliferative Capacity ◽

Spinal Cord Development

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RalGAPα1is dispensable for embryonic cortical morphogenesisin mice

10.21203/rs.3.rs-408297/v1 ◽

2021 ◽

Author(s):

Yingqian Xia ◽

Chaoli Huang ◽

Sangsang Zhu ◽

Qiaoli Chen ◽

Guiquan Chen ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Brain Development ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Cortical Development ◽

Neural Progenitor ◽

Conditional Knockout ◽

Deletion Syndrome ◽

The Central Nervous System

Abstract Background: Cortical morphogenesis is a complex process and involves a large number of genes. RalGAPα1 gene (also called Tulip1 ), mapped to chromosome 14q13.2, is a candidate gene for the 14q13 deletion syndrome associated with delayed brain development. However, it remains unknown whether RalGAPα1 directly regulates cortical development. Methods: To address the above question, we generated neural progenitor cells (NPCs) specific RalGAPα1 conditional knockout (cKO) mice through crossing RalGAPα1 f/f to Nestin-Cre transgenic (Tg) mice in which the Cre recombinase is expressed in neural progenitor cells and derived neurons in the central nervous system (CNS) since very early stage of development. Morphological, biochemistry and immunohistochemistry (IHC) methods were used to evaluate brain development. Results: We found that the brain size, shape and cortical laminations were comparable between control and RalGAPα1 cKO mice. Moreover, the populations and proliferations of NPCs in the ventricular and subventricular zones were not different between control and RalGAPα1 cKO cortices. Conclusions: Inactivation of RalGAPα1 in the central nervous system in murine model does not significantly affect the embryonic cortical development. Keywords: RalGAPα1 ; cortical development; neural progenitor cells; neurodevelopmental disease

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Erythropoietin receptor signalling is required for normal brain development

Development ◽

10.1242/dev.129.2.505 ◽

2002 ◽

Vol 129 (2) ◽

pp. 505-516 ◽

Cited By ~ 1

Author(s):

Xiaobing Yu ◽

John J. Shacka ◽

Jeffrey B. Eells ◽

Carlos Suarez-Quian ◽

Ronald M. Przygodzki ◽

...

Keyword(s):

Brain Development ◽

Cell Survival ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Erythropoietin Receptor ◽

Receptor Expression ◽

Neuroprotective Activity ◽

Null Mouse ◽

Embryonic Brain

Erythropoietin, known for its role in erythroid differentiation, has been shown to be neuroprotective during brain ischaemia in adult animal models. Although high levels of erythropoietin receptor are produced in embryonic brain, the role of erythropoietin during brain development is uncertain. We now provide evidence that erythropoietin acts to stimulate neural progenitor cells and to prevent apoptosis in the embryonic brain. Mice lacking the erythropoietin receptor exhibit severe anaemia and defective cardiac development, and die at embryonic day 13.5 (E13.5). By E12.5, in addition to apoptosis in foetal liver, endocardium and myocardium, the erythropoietin receptor null mouse shows extensive apoptosis in foetal brain. Lack of erythropoietin receptor affects brain development as early as E10.5, resulting in a reduction in the number of neural progenitor cells and increased apoptosis. Corresponding in vitro cultures of cortical cells from Epor–/– mice also exhibited decreases in neuron generation compared with normal controls and increased sensitivity to low oxygen tension with no surviving neurons in Epor–/– cortical cultures after 24 hour exposure to hypoxia. The viability of primary Epor+/+ rodent embryonic cortical neurons was further increased by erythropoietin stimulation. Exposure of these cultures to hypoxia induced erythropoietin expression and a tenfold increase in erythropoietin receptor expression, increased cell survival and decreased apoptosis. Cultures of neuronal progenitor cells also exhibited a proliferative response to erythropoietin stimulation. These data demonstrate that the neuroprotective activity of erythropoietin is observed as early as E10.5 in the developing brain, and that induction of erythropoietin and its receptor by hypoxia may contribute to selective cell survival in the brain.

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Developing Human Pluripotent Stem Cell-Based Cerebral Organoids with a Controllable Microglia Ratio for Modeling Brain Development and Pathology

10.1101/2020.10.09.331710 ◽

2020 ◽

Author(s):

Ranjie Xu ◽

Andrew J. Boreland ◽

Xiaoxi Li ◽

Caroline Erickson ◽

Mengmeng Jin ◽

...

Keyword(s):

Brain Development ◽

Progenitor Cells ◽

Neural Progenitor Cells ◽

Developmental Stages ◽

Proper Time ◽

Super Resolution ◽

Neural Progenitor ◽

Human Microglia ◽

Brain Organoid

AbstractMicroglia, as brain-resident macrophages, play critical roles in brain development, homeostasis, and disease. Microglia in animal models cannot accurately model the properties of human microglia due to notable transcriptomic and functional differences between human and other animal microglia. Efficient generation of microglia from human pluripotent stem cells (hPSCs) provides unprecedented opportunities to study the function and behavior of human microglia. Particularly, incorporating hPSCs-derived microglia into brain organoids facilitates their development in a 3-dimensional context, mimicking the brain environment. However, an optimized method that integrates an appropriate amount of microglia into brain organoids at a proper time point, resembling in vivo brain development, is still lacking. Here, we report the development of a new brain region-specific, microglia-containing organoid model by co-culturing hPSCs-derived primitive neural progenitor cells (pNPCs) and primitive macrophage progenitors (PMPs). In these organoids, hPSCs-derived pNPCs and PMPs interact with each other and develop into functional neurons, astroglia, and microglia, respectively. Importantly, the numbers of human microglia in the organoids can be controlled, resulting in a cell type ratio similar to that seen in the human brain. Using super-resolution microscopy, we demonstrate that these human microglia are able to phagocytize neural progenitor cells (NPCs) and dead cells, as well as to prune synapses at different developmental stages of the organoids. Furthermore, these human microglia respond to Zika virus infection of the organoids, as indicated by amoeboid-like morphology, increased expression of gene transcripts encoding inflammatory cytokines, and excessive pruning of synaptic materials. Together, our findings establish a new microglia-containing brain organoid model that will serve to study human microglial function in a variety of neurological disorders.

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