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Caenorhabditis elegans aristaless/Arx gene alr-1 restricts variable gene expression.

Variable expressivity of mutant phenotypes in genetically identical individuals is a phenomenon widely reported but poorly understood. For example, mutations in the gene encoding the transcription factor ALR-1 in Caenorhabditis elegans result in variable touch receptor neuron (TRN) function. Using single-molecule in situ hybridization, we demonstrate that this phenotypic variability reflects enhanced variability in the expression of the selector gene mec-3, which is needed, together with unc-86, for the differentiation of the TRNs. In a yeast expression system, ALR-1 enhances MEC-3/UNC-86-dependent transcription from the mec-3 promoter, showing that ALR-1 can enhance bulk mec-3 expression. We show that, due to stochastic fluctuations, autoregulation of mec-3 is not sufficient for TRN differentiation; ALR-1 provides a second positive feedback loop that increases mec-3 expression, by restricting variability, and thus ensures TRN differentiation. Our results link fluctuations in gene expression to phenotypic variability, which is seen in many mutant strains, and provide an explicit demonstration of how variable gene expression can be curtailed in developing cells to ensure their differentiation. Because ALR-1 and similar proteins (Drosophila Aristaless and human ARX) are needed for the expression of other transcription factors, we propose that proteins in this family may act to ensure differentiation more generally.

Pubmed ID: 21368126

Authors

  • Topalidou I
  • van Oudenaarden A
  • Chalfie M

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 8, 2011

Associated Grants

  • Agency: NIH HHS, Id: DP1 OD003936
  • Agency: NIGMS NIH HHS, Id: GM30997
  • Agency: NIH HHS, Id: OD3936
  • Agency: NIGMS NIH HHS, Id: R01 GM030997

Mesh Terms

  • Animals
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins
  • Gene Expression Regulation
  • Homeodomain Proteins
  • In Situ Hybridization, Fluorescence
  • Mutation
  • Promoter Regions, Genetic
  • Transcription, Genetic