A novel mutant allele of Mta3 in the mouse: genetic analysis of roles in immunity and androgen biology
The metastasis associated (MTA) proteins, encoded in mammals by three highly similar gene paralogs, Mta1, Mta2, and Mta3, are integral components of the nucleosome remodeling deacetylase (NuRD) complex. While biochemical and molecular studies have probed the functions of the Mta gene family, genetic data in animals is less complete. Here we report the creation of a novel allele of Mta3 in which the first two coding exons, which encode the bromo-adjacent homology (BAH) domain of Mta3, are deleted. Animals homozygous for this Mta3DBAH allele are viable, fertile, and have no obvious deleterious phenotype. Exploration of the Mta3DBAH allele revealed that the Mta3 locus has an unannotated promoter located between Mta3 exons 3 and 4, which is unperturbed in the Mta3DBAH allele, which appears to drive expression of an MTA3 protein variant lacking the BAH domain. To explore the genetic relationship of this allele to the paralog Mta1, the Mta3DBAH animals were crossed to animals bearing the Mta1tm1a(EUCOMM)Wtsi allele, no double homozygous mutant animals were recovered, indicating synthetic lethality between these two Mta alleles. To understand the impact of the Mta3DBAH allele on functions previously described ex vivo, studies were performed to examine roles of Mta3 in the immune response and in androgen biology. Mta3DBAH homozygous animals have modest defects in B lymphocyte activation and antibody production, which could result in a selective disadvantage in a natural environment. Conditional mutation in B lymphocytes revealed selection for cells escaping deletion in post germinal center stages of antigen-dependent activation. No genetic requirements for Mta3 in androgen biology in adults were documented, but mutant animals display behavior defects consistent with altered androgen levels during early postnatal life. These studies clarify the genetic requirements for MTA proteins in mammalian development and identify specific functions for MTA3. Overall design: Bulk RNAseq profiling of mouse testis from wild type or Mta3 mutant (lacking BAH domain) genotypes.