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E12.5 Murine lateral cortical progenitor cells: Pax6sey/sey vs. Pax6+/+

ABSTRACT: The mechanisms by which the early spatiotemporal expression patterns of transcription factors such as Pax6 regulate the region-specific proliferation rates of neural progenitors are poorly understood. Pax6 is expressed in a gradient across the developing cortex and is essential for normal corticogenesis. We found that constitutive or conditional loss of Pax6 increases cortical progenitor proliferation by amounts that vary regionally with normal Pax6 levels. We compared the gene expression profiles of equivalent Pax6-expressing progenitors isolated from Pax6+/+ and Pax6-/- cortices and identified many negatively-regulated cell cycle genes including those encoding Cyclins and Cdks. Biochemical assays indicated that Pax6 directly represses Cdk6 expression. Cyclin/Cdk repression inhibits retinoblastoma protein (pRb) phosphorylation, thereby limiting the transcription of genes directly promoting mitosis, and we showed that Pax6 inhibits pRb phosphorylation and represses several genes involved in DNA replication. Our results indicate that Pax6’s modulation of the cell cycles of cortical progenitors is regional and direct.

ORGANISM(S): Mus musculus

PROVIDER: GSE38703 | GEO | 2013/01/31

SECONDARY ACCESSION(S): PRJNA168450

REPOSITORIES: GEO

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E12.5 Murine lateral cortical progenitor cells: Pax6sey/sey vs. Pax6+/+

Project description:The mechanisms by which the early spatiotemporal expression patterns of transcription factors such as Pax6 regulate the region-specific proliferation rates of neural progenitors are poorly understood. Pax6 is expressed in a gradient across the developing cortex and is essential for normal corticogenesis. We found that constitutive or conditional loss of Pax6 increases cortical progenitor proliferation by amounts that vary regionally with normal Pax6 levels. We compared the gene expression profiles of equivalent Pax6-expressing progenitors isolated from Pax6+/+ and Pax6-/- cortices and identified many negatively-regulated cell cycle genes including those encoding Cyclins and Cdks. Biochemical assays indicated that Pax6 directly represses Cdk6 expression. Cyclin/Cdk repression inhibits retinoblastoma protein (pRb) phosphorylation, thereby limiting the transcription of genes directly promoting mitosis, and we showed that Pax6 inhibits pRb phosphorylation and represses several genes involved in DNA replication. Our results indicate that Pax6M-bM-^@M-^Ys modulation of the cell cycles of cortical progenitors is regional and direct. Two condition experiment, Pax6sey/sey vs Pax6+/+ cortical progenitor cells from lateral cortex. 3 biological replicates. Each replicate contains RNA from cells pooled from 4 individual E12.5 embryos

2013-01-31 | E-GEOD-38703 | biostudies-arrayexpress

A dynamic unfolded protein response contributes to the control of cortical neurogenesis

Project description:The cerebral cortex contains layers of neurons sequentially generated by distinct lineage-related progenitors. At the onset of corticogenesis, the first-born progenitors are apical progenitors (APs) whose asymmetric division give birth directly to neurons. Later, they switch to indirect neurogenesis by generating intermediate progenitors (IPs), which give rise to projection neurons of all cortical layers. While a direct lineage relationship between APs and IPs has been established, the molecular mechanism that controls their transition remains elusive. Our data suggest that interfering with codon translation speed triggers endoplasmic reticulum stress and the unfolded protein response (UPR), further impairing the generation of IPs and leading to microcephaly. Moreover, we demonstrate that a progressive downregulation of UPR in cortical progenitors acts as physiological signal to amplify IPs and promotes indirect neurogenesis. Thus, our findings reveal a hitherto unrecognized contribution of UPR to cell fate acquisition during mammalian brain development. Ribosome profiling and RNA-Seq of forebrains from E14.5 mouse embryos from wild type animals and mutants carrying a conditional knockout of ELP3 in cortical progenitors

2015-12-11 | E-GEOD-74683 | biostudies-arrayexpress

Transcriptome and proteome analysis of human brain organoids

Project description:During development of the human cerebral cortex, multipotent neural progenitors generate excitatory neurons and glial cells. Investigations of the transcriptome and epigenome have revealed important gene regulatory networks underlying this crucial developmental event. However, the post-transcriptional control of gene expression and protein abundance during human corticogenesis remains poorly understood. We addressed this issue by using a dual reporter cell line to isolate neural progenitors and neurons from the telencephalic brain organoid tissue and performed cell type and developmental stage-specific transcriptome and proteome analysis. Integrating the two datasets revealed temporal modules of gene expression during human corticogenesis, both at RNA and protein level. Our multiomics approach reveals novel posttranscriptional regulatory mechanisms crucial for fidelity of cortical development.

2022-10-25 | PXD037106 | Pride

Chromatin regulation by BAF170 controls cerebral cortical size and thickness.

Project description:Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that the conditional deletion of BAF170 promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 over-expression results an opposing phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting the euchromatin structure and thereby modulating the binding efficiency of Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture. Cortical gene expression is compared between three E12.5 mouse embryos with cortex-specific loss of BAF170 function and three littermate control embryos.

2013-05-02 | E-GEOD-45629 | biostudies-arrayexpress

The protomap is propagated to cortical plate neurons through an Eomes-dependent intermediate map

Project description:The cortical area map is initially patterned by transcription factor (TF) gradients in the neocortical primordium, which define a protomap in the embryonic ventricular zone (VZ). However, mechanisms that propagate regional identity from VZ progenitors to cortical plate (CP) neurons are unknown. Here we show that the VZ, subventricular zone (SVZ), and CP contain distinct molecular maps of regional identity, reflecting different gene expression gradients in radial glia progenitors, intermediate progenitors, and projection neurons, respectively. The intermediate map in SVZ is modulated by Eomes (also known as Tbr2), a T-box TF. Eomes inactivation caused rostrocaudal shifts in SVZ and CP gene expression, with loss of corticospinal axons and gain of corticotectal projections. These findings suggest that cortical areas and connections are shaped by sequential maps of regional identity, propagated by the Pax6 ? Eomes ? Tbr1 TF cascade. In humans, PAX6, EOMES, and TBR1 have been linked to intellectual disability and autism. To determine the role of Eomes in the propagation of the protomap to cortical plate neurons, used microarray analysis of E14.5 cortex from five wild type and three Eomes knockout mice.

2013-04-02 | E-GEOD-43387 | biostudies-arrayexpress

Pax6 targets in neural stem cells

Project description:Pax6 is a highly conserved transcription factor among vertebrates and is important in various aspects of the central nervous system (CNS) development. However, the gene regulatory circuitry of Pax6 underlying these functions remains elusive. We find that, following expression in neural progenitor cells, Pax6 targets many promoters embedded in an active chromatin environment. Intriguingly, many of these sites are also bound by another progenitor factor, Sox2, which cooperates with Pax6 in gene regulation. A combinatorial analysis of Pax6 binding dataset with transcriptome changes in Pax6-deficient neural progenitors reveals a dual role for Pax6, in which it activates the neuronal (ectodermal) genes while concurrently represses the mesodermal and endodermal genes thereby ensuring the unidirectionality of lineage commitment towards glutamatergic neuronal differentiation. Furthermore, Pax6 is critical for inducing activity of transcription factors that elicit neurogenesis and repress others that promote non-neuronal lineages. In addition to many established downstream effectors, Pax6 directly binds and activates a number of genes that are specifically expressed in neural progenitors but have not been previously implicated in neurogenesis. The in utero knockdown of one such gene, Ift74, during brain development impairs polarity and migration of new-born neurons. These findings demonstrate new aspects of the gene regulatory circuitry of Pax6, revealing how it functions to control neuronal development at multiple levels to ensure unidirectionality and proper execution of the neurogenic program.

2016-05-02 | GSE75255 | GEO

Expression data from wild type and Pax6 null neural progenitors

2016-05-02 | GSE75252 | GEO

Gene expression in basal progenitors in the cerebral cortex of Tbr2 conditional knockout mice

Project description:During cortical development neurons are generated from basal progenitors (BPs) which specifically express the transcription factor Tbr2. We used fluorescent-activated cell sorting (FACS) to isolate BPs from Tbr2-conditional knockout mice brain at early (E13) and late (E16) stages of cortical neurogenesis and determined mRNA expression profiles using microarray (Illumina MouseWG-6 v2). Role of transcription factor Tbr2 in basal progenitors during corticogenesis.

2019-10-12 | GSE121180 | GEO

The Epigenetic Factor Landscape of Developing Neocortex is Regulated by Transcription Factors Pax6→Tbr2→Tbr1

Project description:Epigenetic factors (EFs) regulate multiple aspects of cerebral cortex development, including proliferation, neuronal differentiation, laminar fate, and regional identity. The same neurodevelopmental processes are also regulated by transcription factors (TFs), notably the Pax6→Tbr2→Tbr1 cascade expressed sequentially in radial glial progenitors, intermediate progenitors, and postmitotic projection neurons, respectively. Here, we studied the EF landscape and its regulation in embryonic mouse neocortex. Microarray and in situ hybridization assays revealed that many EF genes are expressed in specific cortical cell types, such as intermediate progenitors, or in rostrocaudal gradients. Furthermore, many EF genes are directly bound and transcriptionally regulated by Pax6, Tbr2, or Tbr1, as determined by chromatin immunoprecipitation-sequencing and gene expression analysis of TF mutant cortices. The results demonstrated that Pax6, Tbr2, and Tbr1 form a direct feedforward genetic cascade, with direct feedback repression. Results also revealed that each TF regulates multiple EF genes that control DNA methylation, histone marks, chromatin remodeling, and noncoding RNA.

2018-07-30 | GSE115703 | GEO

MicroRNA expression in a model of mouse corticogenesis

Project description:We established an in vitro model of mouse corticogenesis starting from mouse embryonic stem cells (ESCs). We analyzed miRNAomes of dividing and post-mitotic ESC-cortical cells and miRNAomes of E12 and P0 mouse cortex. By comparing the microRNA expression profiles of progenitors and precursors at different times of in vitro differentiation to the microRNA expression profiles of E12 and P0 mouse cortex we validated the model of mouse in vitro corticogenesis and provided microRNA expression datasets of early mouse embryonic cerebral cortex. Moreover, by the miR-CATCH method we analyzed the enrichement of microRNAs after the binding to the 3’UTR of Satb2. This allowed to identify microRNAs that directly inhibit SATB2 expression.

2021-04-22 | GSE172502 | GEO

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