A novel mutant allele of Mta3 in the mouse: genetic analysis of roles in immunity and androgen biology.

Abstract

The metastasis associated (MTA) proteins, encoded in mammals by 3 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 2 coding exons, which encode the bromo-adjacent homology (BAH) domain of Mta3, are deleted. Animals homozygous for this Mta3ΔBAH allele are viable, fertile, and have no obvious deleterious phenotype. Exploration of the Mta3ΔBAH allele revealed that the Mta3 locus has an unannotated promoter located between Mta3 exons 3 and 4, which is unperturbed in the Mta3ΔBAH 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 Mta3ΔBAH animals were crossed to animals bearing the Mta1tm1a(EUCOMM)Wtsi allele, no double homozygous mutant animals were recovered, indicating synthetic lethality between these 2 Mta alleles. To understand the impact of the Mta3ΔBAH allele on functions previously described ex vivo, studies were performed to examine roles of Mta3 in the immune response and in androgen biology. Mta3ΔBAH 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. Although adult Mta3ΔBAH animals did not exhibit androgen dysregulation, Mta3ΔBAH males displayed sex-dependent behaviors suggesting dysregulation during critical windows of behavioral development. These studies clarify the genetic requirements for MTA proteins in mammalian development and identify specific functions for MTA3.