Requirement of a Myocardin-Related Transcription Factor for Development of Mammary Myoepithelial Cells

Abstract

ABSTRACT The mammary gland consists of a branched ductal system comprised of milk-producing epithelial cells that form ductile tubules surrounded by a myoepithelial cell layer that provides contractility required for milk ejection. Myoepithelial cells bear a striking resemblance to smooth muscle cells, but they are derived from a different embryonic cell lineage, and little is known of the mechanisms that control their differentiation. Members of the myocardin family of transcriptional coactivators cooperate with serum response factor to activate smooth muscle gene expression. We show that female mice homozygous for a loss-of-function mutation of the myocardin-related transcription factor A ( MRTF-A ) gene are unable to effectively nurse their offspring due to a failure in maintenance of the differentiated state of mammary myoepithelial cells during lactation, resulting in apoptosis of this cell population, a consequent inability to release milk, and premature involution. The phenotype of MRTF-A mutant mice reveals a specific and essential role for MRTF-A in mammary myoepithelial cell differentiation and points to commonalities in the transcriptional mechanisms that control differentiation of smooth muscle and myoepithelial cells.