The Basic Helix-Loop-Helix Genehesr2Promotes Gliogenesis in Mouse Retina

Abstract

Members of a subclass of hairy/Enhancer of split [E(spl)] homologs, called hesr genes, are structurally related to another subclass of hairy/E(spl) homologs, Hes genes, which play an important role in neural development. To characterize the roles of hesr genes in neural development, we used the retina as a model system. In situ hybridization analysis indicated that all hesr genes are expressed in the developing retina, but only hesr2 expression is associated spatially with gliogenesis. Each member was then misexpressed with retrovirus in the retinal explant cultures prepared from mouse embryos or neonates, which well mimic in vivo retinal development. Interestingly, hesr2 but not hesr1 or hesr3 promoted gliogenesis while inhibiting rod genesis without affecting cell proliferation or death, suggesting that the cells that normally differentiate into rods adopted the glial fate by misexpression of hesr2. The gliogenic activity of hesr2 was more profound when it was misexpressed postnatally than prenatally. In addition, double mutation of the neuronal determination genes Mash1 and Math3, which increases Mü ller glia at the expense of bipolar cells, upregulated hesr2 expression. These results indicate that, among structurally related hesr genes, only hesr2 promotes glial versus neuronal cell fate specification in the retina and that antagonistic regulation between hesr2 and Mash1-Math3 may determine the ratios of neurons and glia.

Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma

“…Several molecular mechanisms have been found to be involved in the differentiation of multipotent neural stem cells into different brain cell types. Neurogenic bHLH transcription factors like neurogenin 1/2 and Mash1, a murine homolog of ASCL1, have been shown to inhibit glial differentiation (Furukawa et al, 2000;Zhou et al, 2000;Nieto et al, 2001;Novitch et al, 2001;Satow et al, 2001;Sun et al, 2001). The cytokine leukemia inhibitory factor promotes astroglial differentiation through JAK-STAT signaling pathway (Johe et al, 1996;Bonni et al, 1997).…”

Helt, a Novel Basic-Helix-Loop-Helix Transcriptional Repressor Expressed in the Developing Central Nervous System

“…The capability of Helt to heterodimerize with Hes5 suggests a possible role in the inhibition of Hes5 function since Hes6 inhibits Hes1 function to promote neurogenesis (22,23,24). Alternatively, Helt may inhibit glial differentiation since Hey2 regulates gliogenesis in the developing retina (44). Identification of the downstream target genes of Helt may help to elucidate the role of Helt in central nervous system development.…”

The Evolution of the Neural Basic Helix-Loop-Helix Proteins

“…Cell fate allocations use both extrinsic and intrinsic cues [108], among which is the expression of several bHLH genes, ASH genes [96,109,110,111], ngn genes [70,112], NeuroD and relatives [98,113], and ATH5[58, 111,114]. Several HES bHLH genes are also expressed in the retina [115,116,117,118,119]. HES proteins (also sometimes called ESR or HER proteins) and their orthologs in Drosophila (e.g., Hairy, deadpan, Hey, and the Enhancer of split genes) form a monophyletic group of bHLH ( Fig.…”