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A long lost key opens an ancient lock: Drosophila Myb causes a synthetic multivulval phenotype in nematodes
Paul J Vorster1, Paul Goetsch2, Tilini U Wijeratne3
1Departments of Pathology, Genetics, and Biology, Stanford University, Stanford, CA 94305-5324, USA.
Abstract:
The five-protein MuvB core complex is highly conserved in animals. This nuclear complex interacts with RB-family tumor suppressor proteins and E2F-DP transcription factors to form DREAM complexes that repress genes that regulate cell cycle progression and cell fate. The MuvB core complex also interacts with Myb family oncoproteins to form the Myb-MuvB complexes that activate many of the same genes. We show that animal-type Myb genes are present in Bilateria, Cnidaria and Placozoa, the latter including the simplest known animal species. However, bilaterian nematode worms lost their animal-type Myb genes hundreds of millions of years ago. Nevertheless, amino acids in the LIN9 and LIN52 proteins that directly interact with the MuvB-binding domains of human B-Myb and Drosophila Myb are conserved in Caenorhabditiselegans Here, we show that, despite greater than 500 million years since their last common ancestor, the Drosophila melanogaster Myb protein can bind to the nematode LIN9-LIN52 proteins in vitro and can cause a synthetic multivulval (synMuv) phenotype in vivo This phenotype is similar to that caused by loss-of-function mutations in C. elegans 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 Drosophila Myb that disrupt its functions in vitro and in vivo also disrupt these activities in C. elegans 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.
Insights
Despite losing animal-type Myb genes, nematode worms retain conserved MuvB-binding proteins. Drosophila Myb protein can still bind nematode proteins, activating transcription and causing a synthetic multivulval phenotype in C. elegans.
Area of Science:
- Molecular Biology
- Developmental Biology
- Evolutionary Biology
Background:
- The MuvB core complex is crucial for regulating cell cycle and fate by interacting with RB-family proteins and E2F-DP transcription factors to form DREAM complexes.
- Myb-MuvB complexes, formed by MuvB core and Myb oncoproteins, activate the same genes repressed by DREAM complexes.
- Animal-type Myb genes are found across various animal phyla, but were lost in bilaterian nematode worms over 500 million years ago.
Purpose of the Study:
- To investigate the functional interaction between Drosophila Myb and nematode MuvB core components (LIN9 and LIN52) despite evolutionary divergence.
- To determine if Drosophila Myb can substitute for the lost animal-type Myb function in C. elegans.
- To understand the evolutionary conservation of Myb-MuvB interactions and their role in gene regulation.
Main Methods:
- In vitro binding assays to test the interaction between Drosophila melanogaster Myb and Caenorhabditis elegans LIN9-LIN52 proteins.
- In vivo studies in C. elegans to assess the phenotypic effects of Drosophila Myb expression, specifically looking for the synthetic multivulval (synMuv) phenotype.
- Site-directed mutagenesis of Drosophila Myb's MuvB-binding domain to evaluate the functional importance of specific amino acid residues.
Main Results:
- Drosophila melanogaster Myb protein successfully binds to Caenorhabditis elegans LIN9-LIN52 proteins in vitro.
- Expression of Drosophila Myb in C. elegans induces a synthetic multivulval (synMuv) phenotype, mimicking the effects of mutations in endogenous synMuvB-class genes.
- Amino acid substitutions in the MuvB-binding domain of Drosophila Myb that impair its function in vitro and in vivo also abolish its activity in the nematode system.
Conclusions:
- Conserved interaction sites between Myb proteins and MuvB core components persist even after the loss of animal-type Myb genes, as demonstrated by the Drosophila-nematode interaction.
- Drosophila Myb can functionally interact with nematode MuvB proteins to regulate gene expression, suggesting a conserved mechanism for Myb-MuvB complex function.
- The findings suggest the existence of alternative proteins in nematodes that may fulfill the role of Myb in activating transcription of genes normally repressed by DREAM complexes.
