Dataset Information

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

ABSTRACT: 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).

SUBMITTER: Liu A

PROVIDER: S-EPMC1618116 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Aixiao A Li Jiadong J Marin-Husstege Mireya M Kageyama Ryochiro R Fan Yongjun Y Gelinas Celine C Casaccia-Bonnefil Patrizia P

The EMBO journal 20060928 20

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 ...[more]

PMID: 17006542

Similar Datasets

Project description:Antipsychotic drugs targeting dopamine neurotransmission are still the principal mean of therapeutic intervention for schizophrenia. However, about one third of people do not respond to dopaminergic antipsychotics. Genome wide association studies (GWAS), have shown that multiple genetic factors play a role in schizophrenia pathophysiology. Most of these schizophrenia risk variants are not related to dopamine or antipsychotic drugs mechanism of action. Genetic factors have also been implicated in defining response to antipsychotic medication. In contrast to disease risk, variation of genes coding for molecular targets of antipsychotics have been associated with treatment response. Among genes implicated, those involved in dopamine signaling mediated by D2-class dopamine receptor, including DRD2 itself and its molecular effectors, have been implicated as key genetic predictors of response to treatments. Studies have also reported that genetic variation in genes coding for proteins that cross-talk with DRD2 at the molecular level, such as AKT1, GSK3B, Beta-catenin, and PPP2R2B are associated with response to antipsychotics. In this review we discuss the relative contribution to antipsychotic drug responsiveness of candidate genes and GWAS identified genes encoding proteins involved in dopamine responses. We also suggest that in addition of these older players, a deeper investigation of new GWAS identified schizophrenia risk genes such as FXR1 can provide new prospects that are not clearly engaged in dopamine function while being targeted by dopamine-associated signaling molecules. Overall, further examination of genes proximally or distally related to signaling mechanisms engaged by medications and associated with disease risk and/or treatment responsiveness may uncover an interface between genes involved in disease causation with those affecting disease remediation. Such a nexus would provide realistic targets for therapy and further the development of genetically personalized approaches for schizophrenia.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets