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 cell 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.
Highlights
The cyclin-dependent kinase inhibitor p57KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development
In order to determine the degree of cell-autonomy of imprinted Cdkn1c gene function in cortical development, we used genetic Mosaic Analysis with Double Markers (MADM) paradigms[17,18,19]
Here we report that the Cdkn1c genomic locus, rather than the Cdkn1c transcript, is cell-autonomously required for the survival of radial glia progenitor (RGP) and nascent projection neurons in the developing cerebral cortex
Summary
The cyclin-dependent kinase inhibitor p57KIP2 is encoded by the imprinted Cdkn1c locus, exhibits maternal expression, and is essential for cerebral cortex development. The function of Cdkn1c in corticogenesis may involve substantial noncell-autonomous components which could promote or inhibit RGP-mediated neuron output and/or neuronal maturation. We address this issue and analyze the cell-autonomous phenotypes upon genetic Cdkn1c gene ablation at single-cell level by capitalizing on mosaic analysis with double markers (MADM) technology. We reveal a growth-promoting cell-autonomous Cdkn1c function, which at the mechanistic level acts to protect cells from p53-mediated apoptosis This cell-autonomous Cdkn1c survival function is dosage sensitive but not subject to genomic imprinting and is attributed to the genomic Cdkn1c genomic locus rather than the expressed Cdkn1c transcript
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