Expression Dynamics and Functions of Hes Factors in Development and Diseases

Abstract

Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1 to Hes7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences while the HLH region forms homo-and hetero-dimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits co-repressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate determination steps of embryonic stem cells and neural progenitor cells. Here we discuss some key features of Hes factors in development and diseases.

An Hdac1/Rpd3-Poised Circuit Balances Continual Self-Renewal and Rapid Restriction of Developmental Potential during Asymmetric Stem Cell Division

“…Consistent with this possibility, we found that Klu, Dpn and E(spl)mγ directly bind conserved sites in the 9D11 2-5 enhancer in vitro (Figures 3A and 3E; Supplementary Figures 3A-C). Dpn and E(spl)mγ are evolutionarily conserved transcriptional repressors, but how Klu regulates gene expression is less clear (Kobayashi and Kageyama, 2014; Taelman et al, 2004; Zacharioudaki et al, 2012). We generated a series of UAS transgenes that encode Klu zf (the Klu DNA-binding zinc-finger motif only), VP16::Klu zf (a constitutive transcriptional activator) or ERD::Klu zf (a constitutive transcriptional repressor).…”

Dynamic Ligand Discrimination in the Notch Signaling Pathway

“…Cleaved NICD has a short half-life, enabling its concentration to respond rapidly to changes in Notch activation (Fryer et al, 2004; Housden et al, 2013; Ilagan et al, 2011). Similarly, the canonical Notch target genes Hes1 and Hes5 have short mRNA and protein half-lives and their levels oscillate in many contexts (Kobayashi and Kageyama, 2014). While dynamics has been shown to play critical roles in other signaling contexts (Purvis and Lahav, 2013), it has not been systematically investigated in the Notch pathway.…”

Neurog1 can partially replace Atoh1 to differentiate and maintain hair cells in a disorganized organ of Corti

“…Atoh1 expression in HCs regulates the expression of genes in the Delta/Notch signaling pathway that are necessary for the development of the surrounding SCs and maintains the proper patterning of the OC (Kobayashi and Kageyama, 2014;Sprinzak et al, 2011;Yamamoto et al, 2014). Lack of the Notch ligand Jag1 results in extra rows of IHCs and the loss of OHCs (Brooker et al, 2006;Kiernan et al, 2006).…”