Hes6 Inhibits Astrocyte Differentiation and Promotes Neurogenesis through Different Mechanisms

The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neuron...

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Bibliographic Details
Published in:The Journal of neuroscience 2006-10, Vol.26 (43), p.11061-11071
Main Authors: Jhas, Sumit, Ciura, Sorana, Belanger-Jasmin, Stephanie, Dong, Zhifeng, Llamosas, Estelle, Theriault, Francesca M, Joachim, Kerline, Tang, Yeman, Liu, Lauren, Liu, Jisheng, Stifani, Stefano
Format: Article
Language:English
Subjects:
Animals
Astrocytes - cytology
Astrocytes - metabolism
Basic Helix-Loop-Helix Transcription Factors - biosynthesis
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - physiology
Cell Differentiation - physiology
Cell Line
Cells, Cultured
Growth Inhibitors - physiology
Humans
Mice
Neural Inhibition - physiology
Repressor Proteins - biosynthesis
Repressor Proteins - genetics
Repressor Proteins - physiology
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Summary:The mechanisms regulating the generation of cell diversity in the mammalian cerebral cortex are beginning to be elucidated. In that regard, Hairy/Enhancer of split (Hes) 1 and 5 are basic helix-loop-helix (bHLH) factors that inhibit the differentiation of pluripotent cortical progenitors into neurons. In contrast, a related Hes family member termed Hes6 promotes neurogenesis. It is shown here that knockdown of endogenous Hes6 causes supernumerary cortical progenitors to differentiate into cells that exhibit an astrocytic morphology and express the astrocyte marker protein GFAP. Conversely, exogenous Hes6 expression in cortical progenitors inhibits astrocyte differentiation. The negative effect of Hes6 on astrocyte differentiation is independent of its ability to promote neuronal differentiation. We also show that neither its proneuronal nor its anti-gliogenic functions appear to depend on Hes6 ability to bind to DNA via the basic arm of its bHLH domain. Both of these activities require Hes6 to be localized to nuclei, but only its anti-gliogenic function depends on two short peptides, LNHLL and WRPW, that are conserved in all Hes6 proteins. These findings suggest that Hes6 is an important regulator of the neurogenic phase of cortical development by promoting the neuronal fate while suppressing astrocyte differentiation. They suggest further that separate molecular mechanisms underlie the proneuronal and anti-gliogenic activities of Hes6 in cortical progenitor cells.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.1358-06.2006