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Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development [cdkn1c_KO]

ABSTRACT: The cyclin-dependent kinase inhibitor p57KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development. How Cdkn1c regulates corticogenesis is however not clear. To this end we employ Mosaic Analysis with Double Markers (MADM) technology to genetically dissect Cdkn1c gene function in corticogenesis at single cell resolution. We find that the previously described growth-inhibitory Cdkn1c function is a non-cell-autonomous one, acting on the whole organism. In contrast we reveal a growth-promoting cell-autonomous Cdkn1c function which at the mechanistic level mediates radial glial progenitor and nascent projection neuron survival. Strikingly, the growth-promoting function of Cdkn1c is highly dosage sensitive but not subject to genomic imprinting. Collectively, our results suggest that the Cdkn1c locus regulates cortical development through distinct cell-autonomous and non-cell-autonomous mechanisms. More generally, our study highlights the importance to probe the relative contributions of cell intrinsic gene function and tissue-wide mechanisms to the overall phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE138228 | GEO | 2020/01/21

REPOSITORIES: GEO

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Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development

Project description:The cyclin-dependent kinase inhibitor p57KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development. How Cdkn1c regulates corticogenesis is however not clear. To this end we employ Mosaic Analysis with Double Markers (MADM) technology to genetically dissect Cdkn1c gene function in corticogenesis at single cell resolution. We find that the previously described growth-inhibitory Cdkn1c function is a non-cell-autonomous one, acting on the whole organism. In contrast we reveal a growth-promoting cell-autonomous Cdkn1c function which at the mechanistic level mediates radial glial progenitor and nascent projection neuron survival. Strikingly, the growth-promoting function of Cdkn1c is highly dosage sensitive but not subject to genomic imprinting. Collectively, our results suggest that the Cdkn1c locus regulates cortical development through distinct cell-autonomous and non-cell-autonomous mechanisms. More generally, our study highlights the importance to probe the relative contributions of cell intrinsic gene function and tissue-wide mechanisms to the overall phenotype.

2020-01-21 | GSE138227 | GEO

Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development [Cdkn1c_allelic expression]

2019-12-03 | GSE138229 | GEO

Knockdown of CDKN1C (p57kip2) and PHLDA2 results in developmental changes in bovine pre-implantation embryos

Project description:Transcriptome of CDKN1C-siRNA-injected embryos were compared to sham-injected embryos using RNA-sequencing to determine the genes and pathways downstream of the silenced gene that may have been altered. Transcriptome comparison between two pools of embryos (i.e. CDKN1C-siRNA-injected vs sham-injected embryos)

2012-12-15 | E-GEOD-42931 | biostudies-arrayexpress

Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development

Project description:Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development

| PRJNA575159 | ENA

Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development

Project description:Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development

| PRJNA575163 | ENA

Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development [cdkn1c_KO]

Project description:Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development [cdkn1c_KO]

| PRJNA575162 | ENA

Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development [Cdkn1c_allelic expression]

Project description:Imprinted Cdkn1c Genomic Locus Cell-Autonomously Promotes Cell Survival in Cerebral Cortex Development [Cdkn1c_allelic expression]

| PRJNA575164 | ENA

Conservation of parental genomic imprinting by cortex generated from embryonic stem cells [RRBS-seq]

Project description:In vitro cortex generated from embryonic stem cells (ESCs) is a model system to investigate corticogenesis and a promising tool for cortical therapy. A fundamental question that has implications for understanding corticogenesis and for using stem cells therapeutically is to determine whether in vitro cortex reproduces some fine-tuned epigenetic modifications that are important for corticogenesis and function in vivo such as parent-of-origin dependent DNA methylation and expression of imprinted genes (IGs). Here, we have compared at single-base resolution the parent-of-origin dependent DNA methylation and expression of IGs in hybrid cortices generated either in vivo or in vitro from ESCs using Reduced Representation Bisulfite Sequencing (RRBS) and RNA-seq. We report that in vitro cortex strictly reproduced the in vivo parental expression of 41 IGs, including those involved in corticogenesis such as Mest (paternal) and Cdkn1c (maternal). The expressed allele was set in ESCs and maintained during in vitro corticogenesis for most IGs but some switched from a biallelic expression in ESCs to the monoallelic expression observed in vivo. RRBS experiments revealed that parent-of-origin dependent methylation at imprinted loci were also largely similar in in vitro and in vivo cortices except at a few loci. The most discordant locus was Gpr1-Zdbf2: Zdbf2 RNA was paternal in vivo and biallelic in vitro, and this was concomitant with an aberrant gain of methylation on the maternal allele in vitro. Thus, we conclude that the epigenetic mechanisms at imprinted loci are largely but not strictly preserved in vitro. We propose that in vitro corticogenesis, with its set of IGs displaying faithful parent-of-origin dependent expression and methylation, helps to define the poorly known mechanisms regulating imprinting in the brain and roles of IGs during corticogenesis.

2016-04-21 | GSE75485 | GEO

Gene expression analysis of human cell lines established from normal patient's fibroblast and BWS patients with known mutations in the CDKN1C and KCNQ1OT1

Project description:Gene expression profiling was carried out in one normal human fibroblast cell line established from normal people and three different cell lines established from BWS patients to characterize the molecular mechanisms relevant to the etiology of BWS and tumor development. Whole-transcriptome sequencing of three BWS fibroblastic cell lines was established from patients with mutation in the CDKN1C mutation (CDKN1C+ cell line), and loss of methylation in the KCNQ1OT1 region (KvDMR+ cell line: with KvDMR molecular defect, and KvDMR- cell line: absence of KvDMR molecular defect but it had some clinical signs of BWS)

2016-04-30 | GSE69737 | GEO

Genome-wide analysis of SNB19 and SHSY5Y cells with single or double knockdown of SDHD and CDKN1C or SLC22A18

Project description:Analysis of knockdown of SDHD with or without knockdown of CDKN1C or SLC22A18 at gene expression level. The hypothesis tested in this study was to determine whether the gene expression signature following SDHD knockdown together with SLC22A18 or CDKN1C more closely resembles the signature found in tumors than the signature resulting from SDHD knockdown alone.

2016-05-01 | GSE80968 | GEO

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