RESUMO
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.
Assuntos
Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica no Desenvolvimento , Glândulas Mamárias Animais/crescimento & desenvolvimento , Prolactina/fisiologia , Proteínas Supressoras da Sinalização de Citocina/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ligação a DNA/análise , Proteínas de Ligação a DNA/metabolismo , Feminino , Perfilação da Expressão Gênica , Lactação/genética , Glândulas Mamárias Animais/química , Glândulas Mamárias Animais/efeitos dos fármacos , Camundongos , Camundongos Knockout , Gravidez , Prolactina/farmacologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptores da Prolactina/genética , Proteínas Supressoras da Sinalização de Citocina/análise , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Fatores de Transcrição/análise , Fatores de Transcrição/metabolismo , Transcrição GênicaRESUMO
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.