A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players.
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).
Liu
Aixiao
A
Department of Neuroscience and Cell Biology, UMDNJ, Piscataway, NJ 08854, USA.
Li
Jiadong
J
Marin-Husstege
Mireya
M
Kageyama
Ryochiro
R
Fan
Yongjun
Y
Gelinas
Celine
C
Casaccia-Bonnefil
Patrizia
P
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D055757:SOXE Transcription Factors; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D012097:Repressor Proteins; D055757:SOXE Transcription Factors; D014157:Transcription Factors; C065500:ASCL1 protein, human; C489685:Hes5 protein, mouse; C527924:Sox10 protein, mouse