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Negative autoregulation of Mash1 expression in CNS development
1Center for Basic Neuroscience, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas, 75235-9111, USA.
Developmental Biology
|June 6, 2000
Summary
Mash1 (MASH1) transcription factor normally represses its own gene expression, unlike other proneural proteins. This negative autoregulation is indirect, potentially involving HES-mediated repression.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Mash1 is a neural-specific transcription factor crucial for central and peripheral nervous system development.
- Elevated Mash1 transcription in Mash1-null mice suggests negative autoregulation, contrasting with other proneural bHLH proteins.
Purpose of the Study:
- To investigate the mechanisms underlying Mash1's negative autoregulation.
- To identify cis-regulatory elements responsible for Mash1's self-repression.
Main Methods:
- Utilized Mash1/lacZ transgenes with varying lengths of flanking cis-regulatory sequences.
- Introduced mutations in E-box and HES consensus sites within regulatory regions.
- Analyzed lacZ expression in Mash1 mutant backgrounds.
Main Results:
- A 36-kb Mash1/lacZ transgene showed increased expression in Mash1 mutants, confirming negative autoregulation.
- Autoregulatory elements colocalized with a 1.2-kb CNS enhancer.
- Mutations in E-box sites did not abolish autoregulation, indicating MASH1 does not directly repress its own transcription.
- HES site mutations also did not affect autoregulation.
Conclusions:
- Mash1 likely represses its own transcription indirectly, not through direct binding to E-boxes.
- The mechanism may involve HES-mediated repression of positive regulators or novel HES binding sites.
- This indirect negative autoregulation differs from typical proneural bHLH protein behavior.