Adipocyte derived paracrine mediators of mammary ductal morphogenesis controlled by retinoic acid receptors

作者：Marzan Christine V; Kupumbati Tara S; Bertran Silvina P; Samuels TraceyAnn; Leibovitch Boris; Mira y Lopez Rafael; Ossowski Liliana; Farias Eduardo F^*

来源：Developmental Biology, 2011, 349(2): 125-136.

DOI：10.1016/j.ydbio.2010.10.018

• RARs
• Adipocytes
• Paracrine
• Mammary morphogenesis
• Pleiotrophin

We generated a transgenic (Tg)-mouse model expressing a dominant negative-(DN)-RAR alpha, (RAR alpha G303E) under adipocytes-specific promoter to explore the paracrine role of adipocyte retinoic acid receptors (RARs) in mammary morphogenesis. Transgenic adipocytes had reduced level of RAR alpha, beta and gamma, which coincided with a severely underdeveloped pubertal and mature ductal tree with profoundly decreased epithelial cell proliferation. Transplantation experiments of mammary epithelium and of whole mammary glands implicated a fat-pad dependent paracrine mechanism in the stunted phenotype of the epithelial ductal tree. Co-cultures of primary adipocytes, or in vitro differentiated adipocyte cell line, with mammary epithelium showed that when activated, adipocyte-RARs contribute to generation of secreted proliferative and pro-migratory factors. Gene expression microarrays revealed a large number of genes regulated by adipocyte-RARs. Among them, pleiotrophin (PTN) was identified as the paracrine effectors of epithelial cell migration. Its expression was found to be strongly inhibited by DN-RAR alpha, an inhibition relieved by pharmacological doses of all-trans retinoic acid (atRA) in culture and in vivo. Moreover, adipocyte-PTHR, another atRA responsive gene, was found to be an up-stream regulator of PTN. Overall, these results support the existence of a novel paracrine loop controlled by adipocyte-RAR that regulates the mammary ductal tree morphogenesis.

• 出版日期2011-1-15