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  • The EMBO Journal (2006) 25, 4833 - 4842
  • doi:10.1038/sj.emboj.7601352

Published online: 28 September 2006

A molecular insight of Hes5-dependent inhibition of myelin gene expression: old partners and new players

Aixiao Liu1, Jiadong Li1, Mireya Marin-Husstege1, Ryochiro Kageyama2, Yongjun Fan3, Celine Gelinas3 and Patrizia Casaccia-Bonnefil1

  1. Department of Neuroscience and Cell Biology, UMDNJ, Piscataway, NJ, USA
  2. Institute for Virus Research, Kyoto University, Kyoto, Japan
  3. CABM and Department of Biochemistry, UMDNJ, Piscataway, NJ, USA

Correspondence to:

Patrizia Casaccia-Bonnefil, Department of Neuroscience and Cell Biology, UMDNJ, R Wood Johnson Medical School, 675 Hoes Lane, R 301 Piscataway, NJ 08854, USA. Tel.: +1 732 235 4215; Fax: +1 732 235 4029; E-mail: casaccpa@umdnj.edu

Received 26 May 2006; Accepted 24 August 2006

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).

  • Keywords:

    • development,
    • myelin,
    • Notch,
    • oligodendrocyte,
    • progenitor,
    • transcription