Howard Beatrice, Panchal Heena, McCarthy Afshan, Ashworth Alan
The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London SW3 6JB, United Kingdom.
Genes Dev. 2005 Sep 1;19(17):2078-90. doi: 10.1101/gad.338505.
The mouse scaramanga (ska) mutation impairs mammary gland development such that both abrogation and stimulation of gland formation occurs. We used positional cloning to narrow the interval containing scaramanga (ska) to a 75.6-kb interval containing the distal part of the Neuregulin3 (Nrg3) gene. Within this region the only sequence difference between ska and wild-type mice is in a microsatellite repeat within intron 7. This alteration correlates with variations in Nrg3 expression profiles both at the whole embryo level and locally in the presumptive mammary region in ska mice. Localized expression of Nrg3 and its receptor, Erbb4, in the presumptive mammary region around the future bud site prior to morphological appearance of buds and the expression of bud epithelial markers further support an inductive role. Finally, Neuregulin3 (Nrg3)-soaked beads can induce expression of the early bud marker Lef1 in mouse embryo explant cultures, and epithelial bud formation can be observed histologically, suggesting that initiation of mammary bud development occurs. Taken together, these results indicate that a Neuregulin signaling pathway is involved in specification of mammary gland morphogenesis and support the long-held view that mesenchymal signal(s) are responsible for mammary gland inductive/initiating events.
小鼠斯卡曼加（ska）突变会损害乳腺发育，导致腺体形成既有废除又有刺激的情况发生。我们利用定位克隆将包含斯卡曼加（ska）的区间缩小到一个75.6 kb的区间，该区间包含神经调节蛋白3（Nrg3）基因的远端部分。在这个区域内，ska小鼠和野生型小鼠之间唯一的序列差异在于内含子7中的一个微卫星重复序列。这种改变与ska小鼠整个胚胎水平以及乳腺原基区域局部的Nrg3表达谱变化相关。在芽形态出现之前，Nrg3及其受体Erbb4在未来芽位点周围的乳腺原基区域局部表达，以及芽上皮标记物的表达进一步支持了其诱导作用。最后，用神经调节蛋白3（Nrg3）浸泡过的珠子可以在小鼠胚胎外植体培养物中诱导早期芽标记物Lef1的表达，并且可以通过组织学观察到上皮芽的形成，这表明乳腺芽发育的起始发生了。综上所述，这些结果表明神经调节蛋白信号通路参与了乳腺形态发生的特化，并支持了长期以来的观点，即间充质信号负责乳腺诱导/起始事件。
