Format

Send to

Choose Destination
Dev Biol. 2000 Jun 15;222(2):336-46.

Negative autoregulation of Mash1 expression in CNS development.

Author information

1
Center for Basic Neuroscience, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas, 75235-9111, USA.

Abstract

Mash1, a neural-specific bHLH transcription factor, is essential for the formation of multiple CNS and PNS neural lineages. Transcription from the Mash1 locus is elevated in mice null for Mash1, suggesting that MASH1 normally acts to repress its own transcription. This activity is contrary to the positive autoregulation of other proneural bHLH proteins. To investigate the mechanisms involved in this process, sequences flanking the Mash1 gene were tested for the ability to mediate negative autoregulation. A Mash1/lacZ transgene containing 36 kb of cis-regulatory sequence exhibits an increase in lacZ expression in the Mash1 mutant background, which phenocopies the observation of transcriptional autoregulation at the endogenous Mash1 locus. Using Mash1/lacZ lines with progressively less cis-acting sequence, autoregulatory responsive elements were demonstrated to colocalize with a previously characterized 1.2-kb CNS enhancer. Mutations of E-box sites within this enhancer did not result in an apparent loss of autoregulation, suggesting that MASH1 does not directly repress its own transcription. Interestingly, these mutations did not indicate any underlying positive auto- or cross-regulation of Mash1. Furthermore, the loss of autoregulation in the Mash1 mutant background is reminiscent of a loss of lateral inhibitory signaling. However, mutations in HES consensus sites, the likely purveyors of Notch-mediated lateral inhibition, do not support a role for these sites in negative autoregulation. We hypothesize that MASH1 normally inhibits its own expression indirectly, possibly through a HES-mediated repression of positive regulators or through novel HES binding sites.

PMID:
10837123
DOI:
10.1006/dbio.2000.9697
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center