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

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: GSE138227 | GEO | 2020/01/21

REPOSITORIES: GEO

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

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 | GSE138228 | GEO

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

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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

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

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Cdk5r1_KO_TMT-10plex_brain_cell-autonomous_proteomics

Project description:Concerted radial migration of newly born cortical projection neurons, from their birthplace to their final target lamina, is a key step in the assembly of the cerebral cortex. The cellular and molecular mechanisms regulating radial neuronal migration in vivo are however still unclear, let alone the effects and interactions with the extracellular environment. Recent evidence suggests that distinct signalling cues act cell-autonomously but differentially at particular steps during the overall migration process. Functional MADM (Mosaic Analysis with Double Markers) analyses in comparison to global knockout also indicate a significant degree of non-cell-autonomous and/or community effects in the control of cortical neuron migration. In this project, we established a MADM-based experimental strategy for the quantitative analysis of cell-autonomous gene function versus non-autonomous and/or community effects, focusing on the Cdk5r1 gene, a neuron-specific activator of Cyclin Dependent Kinase 5 known to play a role, among other functions, in neuronal migration during brain development. This dataset corresponds to a TMT-10plex based proteomics analysis of the effects of full or mosaic KO of Cdk5r1 on the neuronal proteome and aims to provide insights into its distinct cell-autonomous and non-autonomous roles in neuronal migration. This dataset and complementary experimental approaches were integrated using computational modelling to define so far unknown cell-autonomous functions of candidate signalling pathways intersecting with non-cell-autonomous effects to coordinate radial neuron migration.

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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]

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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]

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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

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