Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dan L Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Room N1210; BCM600, Houston, TX, 77030, USA.
Center for Cell and Gene Therapy, Texas Children's Feigin Center, Baylor College of Medicine, 1102 Bates Avenue, Houston, TX, 77030, USA.
J Mammary Gland Biol Neoplasia. 2020 Jun;25(2):145-162. doi: 10.1007/s10911-020-09454-3. Epub 2020 Jul 23.
Targeted disruption of the murine Hoxd10 gene (ΔHoxd10) leads to a high frequency of localized (gland-to-gland or regionally within a gland) lactation impairment in homozygous mutant mice as a single gene mutation. The effect of Hoxd10 disruption was enhanced by simultaneous disruption of Hoxd9 (ΔHoxd9/d10), a mutation shown previously to have no effect on mammary function as a single gene alteration. Mammary glands of homozygous ΔHoxd10 and ΔHoxd9/d10 females were indistinguishable from those of wild type littermate and age-matched control mice in late pregnancy. However, in lactation, 47% of homozygous ΔHoxd10 females, and 100% of homozygous ΔHoxd9/d10 females, showed localized or complete failure of two or more glands to undergo lactation-associated morphological changes and to secrete milk. Affected regions of ΔHoxd10 and ΔHoxd9/d10 mutants showed reduced prolactin receptor expression, reduced signal transducer and activator transcription protein 5 (STAT5) phosphorylation, reduced expression of downstream milk proteins, mislocalized glucose transporter 1 (GLUT1), increased STAT3 expression and phosphorylation, recruitment of leukocytes, altered cell cycle status, and increased apoptosis relative to unaffected regions and wild type control glands. Despite these local effects on alveolar function, transplantation results and hormone analysis indicate that Hoxd10 primarily has systemic functions that confer attenuated STAT5 phosphorylation on both wild type and ΔHoxd10 transplants when placed in ΔHoxd10 hosts, thereby exacerbating an underlying propensity for lactation failure in C57Bl/6 mice.
靶向敲除小鼠 Hoxd10 基因（ΔHoxd10）会导致纯合突变小鼠局部（腺体间或腺体内）泌乳功能障碍的频率升高，这是单一基因突变的结果。Hoxd10 敲除的影响通过同时敲除 Hoxd9（ΔHoxd9/d10）而增强，先前的研究表明，该突变作为单一基因突变对乳腺功能没有影响。纯合ΔHoxd10 和 ΔHoxd9/d10 雌性小鼠的乳腺在妊娠晚期与野生型同窝仔鼠和年龄匹配的对照小鼠的乳腺无法区分。然而，在哺乳期，47%的纯合ΔHoxd10 雌性小鼠和 100%的纯合ΔHoxd9/d10 雌性小鼠的两个或多个腺体出现局部或完全泌乳相关形态改变和乳汁分泌失败。ΔHoxd10 和 ΔHoxd9/d10 突变体的受影响区域显示催乳素受体表达减少、信号转导和转录激活因子 5（STAT5）磷酸化减少、下游乳蛋白表达减少、葡萄糖转运蛋白 1（GLUT1）定位错误、STAT3 表达和磷酸化增加、白细胞募集、细胞周期状态改变和凋亡增加，与未受影响的区域和野生型对照腺体相比。尽管这些对肺泡功能的局部影响，但移植结果和激素分析表明，Hoxd10 主要具有系统功能，当放置在ΔHoxd10 宿主中时，会对野生型和ΔHoxd10 移植体均产生减弱的 STAT5 磷酸化，从而加剧 C57Bl/6 小鼠泌乳失败的潜在倾向。
