A Long Lost Key Opens an Ancient Lock:DrosophilaMyb Causes a Synthetic Multivulval Phenotype in Nematodes

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>The five-protein MuvB core complex (LIN9/Mip130, LIN37/Mip40, LIN52, LIN54/Mip120, and LIN53/p55CAF1/RBBP4) has been highly conserved during the evolution of animals. This nuclear complex interacts with proteins encoded by the <jats:italic>RB</jats:italic> tumor suppressor gene family and its associated E2F-DP transcription factors to form DREAM complexes that repress the expression of genes that regulate cell cycle progression and cell fate. The MuvB core complex also interacts with proteins encoded by the <jats:italic>Myb</jats:italic> oncogene family to form the Myb-MuvB complexes that activate many of the same target genes. We show that animal-type <jats:italic>Myb</jats:italic> genes and proteins are present in Bilateria, Cnidaria, and Placozoa, the latter including some of the simplest known animal species. However, bilaterian nematode worms appear to have lost their animal-type <jats:italic>Myb</jats:italic> genes hundreds of millions of years ago. Nevertheless, the amino acids in the LIN9 and LIN52 proteins that directly interact with the MuvB-binding domains of human B-Myb and <jats:italic>Drosophila</jats:italic> Myb are conserved in <jats:italic>C. elegans</jats:italic>. Here we show that, despite greater than 500 million years since their last common ancestor, the <jats:italic>Drosophila melanogaster</jats:italic> Myb protein can bind to the nematode LIN9 and LIN52 family proteins <jats:italic>in vitro</jats:italic> and can cause a synthetic multivulval (synMuv) phenotype <jats:italic>in vivo</jats:italic>. This phenotype is similar to that caused by loss-of-function mutations in <jats:italic>C. elegans</jats:italic> synMuvB class genes including those that encode homologs of the MuvB core, RB, E2F, and DP. Furthermore, amino acid substitutions in the MuvB-binding domain of <jats:italic>Drosophila</jats:italic> Myb that disrupt its functions <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> also disrupt its activity in <jats:italic>C. elegans</jats:italic>. We speculate that nematodes and other animals may contain another protein that can bind to LIN9 and LIN52 in order to activate transcription of genes repressed by DREAM complexes.</jats:p>