Garin Elisabeth, Lemieux Margot, Coulombe Yan, Robinson Gertraud W, Jeannotte Lucie
Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, Canada.
Dev Dyn. 2006 Jul;235(7):1858-71. doi: 10.1002/dvdy.20822.
Recent progress has enlightened the involvement of Hox genes in organogenesis. Several Hox genes are expressed in normal and neoplastic mammary glands. Using Hoxa5 mutant mice, we showed that Hoxa5-/- females present nursing defects. Characterization of the Hoxa5-/- mammary gland phenotype reveals changes in proliferation and differentiation of the epithelium of nulliparous and pregnant Hoxa5-/- females that precede the abnormal secretory activity at parturition. These defects likely underlie the incapacity of Hoxa5-/- dams to properly feed their pups. Hoxa5 expression is restricted to the mammary stroma at specific stages of mammary gland development. The loss of Hoxa5 function causes accelerated lobuloalveolar epithelium development, a phenotype that can be rescued upon grafting of mutant mammary epithelium into wild-type fat pads. Conversely, reciprocal grafting experiments demonstrate that Hoxa5-/- stroma cannot support normal proliferation of wild-type mammary epithelium. These data establish the essential contribution of Hoxa5 to mammary epithelium instruction by means of mesenchymal-epithelial crosstalk.
近期的研究进展揭示了Hox基因在器官发生过程中的作用。若干Hox基因在正常乳腺和肿瘤性乳腺中均有表达。利用Hoxa5突变小鼠，我们发现Hoxa5基因敲除的雌性小鼠存在哺乳缺陷。对Hoxa5基因敲除小鼠乳腺表型的特征分析显示，未生育和怀孕的Hoxa5基因敲除雌性小鼠乳腺上皮细胞的增殖和分化发生了变化，这些变化先于分娩时异常的分泌活动出现。这些缺陷可能是导致Hoxa5基因敲除的母鼠无法正常哺育幼崽的原因。在乳腺发育的特定阶段，Hoxa5的表达局限于乳腺基质。Hoxa5功能的丧失导致小叶腺泡上皮加速发育，将突变的乳腺上皮移植到野生型脂肪垫中可挽救这一表型。相反，反向移植实验表明，Hoxa5基因敲除的基质无法支持野生型乳腺上皮的正常增殖。这些数据证实了Hoxa5通过间充质-上皮细胞相互作用对乳腺上皮指导作用的重要贡献。
