Hes6 Inhibits Astrocyte Differentiation and Promotes Neurogenesis through Different Mechanisms

Abstract

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.

HES6 gene is selectively overexpressed in glioma and represents an important transcriptional regulator of glioma proliferation

“…HES6 expression prevents the precursor-to-astrocyte transition, resulting in an expansion of the neural progenitor cell pool (Jhas et al, 2006). In glioma, HES6 overexpression might maintain the cancer stem cell population as suggested by the increase of nestin expression, although HES6 and nestin or CD133 protein levels were not associated in the current study.…”

“…Hes6 inhibits Hes1 activity by forming heterodimers with Hes1, supports achaete-scute complex homolog-1 (Ascl1) activity and promotes neuronal differentiation (Bae et al, 2000;Koyano-Nakagawa et al, 2000). During cortical neurogenesis and in the presence of astrocyte inducers ciliary neurotrophic factor or leukemia inhibitory factor, HES6 can prevent the precursor-to-astrocyte transition and promote neuronal differentiation through independent mechanisms (Jhas et al, 2006). Progressive astrocytoma and secondary GBM formation are characterized by inhibition of Notch signaling; upregulation of DLL1, ASCL1 and HES6, and uninduced levels of HES1 (Somasundaram et al, 2005).…”

Gene expression profiling identifies Hes6 as a transcriptional target of ATOH1 in cochlear hair cells

“…In fact, it promotes neuronal differentiation in the neural plate [14], the retina [15] and in the cortex [25,26]. However, unlike Atoh1, Hes6 overexpression in the Kö lliker's organ of post-natal rat cochlea does not lead to HC differentiation [11].…”

Coupling of Angiogenesis and Neurogenesis in Cultured Endothelial Cells and Neural Progenitor Cells after Stroke

“…Coupling of angiogenesis and neurogenesis after stroke H Teng et al in the levels of Sox2 mRNA, a gene involved in the maintenance of neural progenitor cell identity (Bani-Yaghoub et al, 2006;Graham et al, 2003), and an increase in the levels of Hes6 mRNA, a gene that promotes neuronal differentiation but inhibits astrocyte differentiation (Gratton et al, 2003;Jhas et al, 2006) (Figure 3). However, when normal SVZ cells were cocultured with stroke RBECs in the growth or differentiation medium in the presence of SU1498, a VEGFR2 antagonist, the number of BrdU + (Figures 2C to E) and Tuj1 + ( Figures 2I, 2J, and 2O) cells was significantly reduced, while the number of GFAP + cells did not significantly change (26.8% ± 1.8% versus 23.5% ± 4.0% in the SU1498 group, Figures 2M, 2N, and 2P).…”