Hormonal cues regulate mammary development, but the consequent transcriptional changes and cell fate decisions are largely undefined. We show that knockout of the prolactin-regulated Ets transcription factor Elf5 prevented formation of the secretory epithelium during pregnancy. Conversely, overexpression of Elf5 in an inducible transgenic model caused alveolar differentiation and milk secretion in virgin mice, disrupting ductal morphogenesis. CD61 + luminal progenitor cells accumulated in Elf5-deficient mammary glands and were diminished in glands with Elf5 overexpression. Thus Elf5 specifies the differentiation of CD61 + progenitors to establish the secretory alveolar lineage during pregnancy, providing a link between prolactin, transcriptional events, and alveolar development.Supplemental material is available at http://www.genesdev.org.

The proliferative phase of mammary alveolar morphogenesis is initiated during early pregnancy by rising levels of serum prolactin and progesterone, establishing a program of gene expression that is ultimately responsible for the development of the lobuloalveoli and the onset of lactation. To explore this largely unknown genetic program, we constructed transcript profiles derived from transplanted mammary glands formed by recombination of prolactin receptor (Prlr) knockout or wild-type mammary epithelium with wild-type mammary stroma. Comparison with profiles derived from prolactin-treated Scp2 mammary epithelial cells produced a small set of commonly prolactin-regulated genes that included the negative regulator of cytokine signaling, Socs2 (suppressor of cytokine signaling 2), and the ets transcription factor, E74-like factor 5 (Elf5). Homozygous null mutation of Socs2 rescued the failure of lactation and reduction of mammary signal transducer and activator of transcription 5 phosphorylation that characterizes Prlr heterozygous mice, demonstrating that mammary Socs2 is a key regulator of the prolactin-signaling pathway. Reexpression of Elf5 in Prlr nullizygous mammary epithelium restored lobuloalveolar development and milk production, demonstrating that Elf5 is a transcription factor capable of substituting for prolactin signaling. Thus, Socs2 and Elf5 are key members of the set of prolactin-regulated genes that mediate prolactin-driven mammary development.

Massive tissue remodelling occurs within the mammary gland during pregnancy, resulting in the formation of lobuloalveoli that are capable of milk secretion. Endocrine signals generated predominantly by prolactin and progesterone operate the alveolar switch to initiate these developmental events. Here we review the current understanding of the components of the alveolar switch and conclude with an examination of the role of the ets transcription factor Elf5. We propose that Elf5 is a key regulator of the alveolar switch. Introduction: the alveolar switchMassive tissue remodelling within the mammary gland during pregnancy results in the formation of the secretory lobuloalveolar units in preparation for lactation. The initial proliferative phase of alveolar morphogenesis is instigated by an increase in the level of serum prolactin (Prl) and progesterone (Pg) [1]. These hormones activate the alveolar switch, a genetic program that coordinates changes in mammary epithelial cell proliferation, migration, differentiation and deletion within the many tissue types of the mammary gland. Here we review our current understanding of the genetic program controlling alveolar morphogenesis, using the mouse as a model of the human breast [2]. We then examine the role played by the ets transcription factor Elf5 in coordinating this program in epithelial cells, and propose that Elf5 is a central component of the alveolar switch. Tissue remodelling during pregnancyThe most striking aspect of mammary development during pregnancy is massive tissue remodelling. During the alveolar morphogenesis phase [3], rapid and global proliferation of the epithelial cells occurs within the ductal branches and developing alveoli. This increases both epithelial cell number and epithelial surface area, actions essential for sufficient milk production during lactation. Cell differentiation becomes dominant from mid-pregnancy as the gland moves into the secretory initiation phase [3]. The developing alveoli cleave and the alveolar cells become polarised and form a spherelike single layer of epithelial cells that envelopes a circular lumen, connected to the ductal network via a single small duct. Each individual alveolus is surrounded by a basket-like architecture of contractile myo-epithelial cells. The myoepithelium of the alveoli is discontinuous so that the luminal cells directly contact the underlying basement membrane, which forms part of the extracellular matrix. Some cells of the ductal network also contact the basement membrane. Contact is required for complete lobuloalveolar differentiation [4,5], seen morphologically by the appearance of lipid droplets [6] and by the initiation of gene expression in a defined order [7]. Nearing parturition, alveolar tight junctions close and milk and colostrum proteins move into the alveolar lumen, in preparation for active milk secretion post-partum, which marks the onset of the secretory activation phase [8] (Figure 1).The epithelial expansion is paralleled by equally dramatic changes in other tissu...