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SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron

Abstract

A series of transcription factors critical for maintenance of the neural stem cell state have been identified1,2,3, but the role of functionally important corepressors4,5,6,7 in maintenance of the neural stem cell state and early neurogenesis remains unclear. Previous studies have characterized the expression of both SMRT (also known as NCoR2, nuclear receptor co-repressor 2) and NCoR in a variety of developmental systems8; however, the specific role of the SMRT corepressor in neurogenesis is still to be determined. Here we report a critical role for SMRT in forebrain development and in maintenance of the neural stem cell state. Analysis of a series of markers in SMRT-gene-deleted mice revealed the functional requirement of SMRT in the actions of both retinoic-acid-dependent and Notch-dependent forebrain development. In isolated cortical progenitor cells, SMRT was critical for preventing retinoic-acid-receptor-dependent induction of differentiation along a neuronal pathway in the absence of any ligand. Our data reveal that SMRT represses expression of the jumonji-domain containing gene JMJD3, a direct retinoic-acid-receptor target that functions as a histone H3 trimethyl K27 demethylase and which is capable of activating specific components of the neurogenic program.

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Figure 1: Impaired neural development in SMRT -/- embryos.
Figure 2: SMRT is a regulator of neural stem cell state.
Figure 3: Individual SMRT -/- neural stem cells are multipotent and require RA receptor for neuronal differentiation.
Figure 4: Derepression of neurogenic genes promotes neuronal differentiation program.

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Acknowledgements

We thank H. Taylor for animal care; C. Nelson for various cell culture assistance; J. Hightower for artwork; M. Fisher for assistance with the manuscript; J. Rossant for providing RARE-LacZ mice; F. Liu for ES cell injections; and the UCSD BIOGEM laboratory (G. Hardiman, director) for array processing and bioinformatics analysis. BIOGEM was supported by an NIH/NIDDK award. M.G.R. is an investigator with the Howard Hughes Medical Institute. H.-J.K. is supported by a post-doctoral fellowship from the Susan G. Komen Foundation. K.J. is supported by a Scientist Development Grant from the American Heart Institute. T.Z. is supported by a post-doctoral fellowship from PCRP of CDMRP. O.H. is supported by grants from VR, CF, BCF and SSF. This work was funded by grants from the NIH to M.G.R.

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Correspondence to Kristen Jepsen.

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Jepsen, K., Solum, D., Zhou, T. et al. SMRT-mediated repression of an H3K27 demethylase in progression from neural stem cell to neuron. Nature 450, 415–419 (2007). https://doi.org/10.1038/nature06270

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