Abstract
T-box proteins are conserved transcription factors that play crucial roles in development of all metazoans; and, in humans, mutations affecting T-box genes are associated with a variety of congenital diseases and cancers. Despite the importance of this transcription factor family, very little is known regarding how T-box factors regulate gene expression. The Caenorhabditis elegans genome contains 21 T-box genes, and their characterized functions include cell fate specification in a variety of tissues. The C. elegans Tbx1 sub-family member MLS-1 functions during larval development to specify the fate of non-striated uterine muscles; and, in mls-1 mutants, uterine muscles are transformed to a vulval muscle fate. Here we demonstrate that MLS-1 function depends on binding to the Groucho-family co-repressor UNC-37. MLS-1 interacts with UNC-37 via a conserved eh1 motif, and the MLS-1 eh1 motif is necessary for MLS-1 to specify uterine muscle fate. Moreover, unc-37 loss-of-function produces uterine muscle to vulval muscle fate transformation similar to those observed in mls-1 mutants. Based on these results, we conclude that MLS-1 specifies uterine muscle fate by repressing target gene expression, and this function depends on interaction with UNC-37. Moreover, we suggest that MLS-1 shares a common mechanism for transcriptional repression with related T-box factors in other animal phyla.
Highlights
T-box transcription factors play essential roles in the development of all multicellular organisms, where their functions include the specification of primary germ layers and the specification of cell fates during organogenesis [1,2]
We show that MLS-1 physically interacts with another conserved protein called Groucho to repress gene expression and that this interaction is necessary for normal MLS-1 function
C. elegans MLS-1 is highly related to T-box factors in humans and other organisms, and we suggest Groucho interaction may be a common mechanism for T-box factor function
Summary
T-box transcription factors play essential roles in the development of all multicellular organisms, where their functions include the specification of primary germ layers and the specification of cell fates during organogenesis [1,2] In humans, both decreased and increased activity of these factors are associated with congenital disease (Holt-Oram syndrome, Ulnar-Mammary syndrome, DiGeorge syndrome, etc) [3], auto immune disorders [4], and cancers [5,6]. Both decreased and increased activity of these factors are associated with congenital disease (Holt-Oram syndrome, Ulnar-Mammary syndrome, DiGeorge syndrome, etc) [3], auto immune disorders [4], and cancers [5,6] Despite this importance the mechanisms by which T-box factors regulate target gene expression are not well established. While this accumulating evidence suggests a variety of Tbox factors interact with Gro/TLE factors, the significance of these interactions has not been examined in vivo
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