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A molecular insight of Hes5‐dependent inhibition of myelin gene expression: old partners and new players
Author(s) -
Liu Aixiao,
Li Jiadong,
MarinHusstege Mireya,
Kageyama Ryochiro,
Fan Yongjun,
Gelinas Celine,
CasacciaBonnefil Patrizia
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601352
Subject(s) - biology , myelin , microbiology and biotechnology , downregulation and upregulation , regulation of gene expression , promoter , activator (genetics) , oligodendrocyte , transcription factor , gene expression , transcriptional regulation , progenitor cell , gene , genetics , stem cell , neuroscience , central nervous system
This study identifies novel mechanisms of Hes5 function in developmental myelination. We report here upregulation of myelin gene expression in Hes5−/− mice compared to wild‐type siblings and downregulation in overexpressing progenitors. This effect was only partially explained by the ability to regulate the levels of Mash1 and bind to N boxes in myelin promoters, as deletion of the DNA‐binding domain of Hes5 did not suppress its inhibitory role on myelin gene expression. Novel mechanisms of Hes5 function in the oligodendrocyte lineage include the regulation of feedback loops with the cell‐specific transcriptional activator Sox10. In progenitors with low levels of Sox10, Hes5 further decreases the bioavailability of this protein by transcriptional inhibition and direct sequestration of this activator. Increasing levels of Sox10 in progenitors, in turn, bind to Hes5 and titrate out its inhibitory effect by sequestration and displacement of the repressive complexes from myelin promoters. Thus, Hes5‐dependent modulation of myelin gene expression involves old players (i.e. Mash1) and novel mechanisms of transcriptional regulation that include cell‐specific regulatory loops with transcriptional activators (i.e. Sox10).