Alk3 controls nephron number and androgen production via lineage-specific effects in intermediate mesoderm
Alk3 controls nephron number and androgen production via lineage-specific effects in intermediate mesoderm
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DOI：
10.1242/dev.059030
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发表时间：
2011-07-01
期刊：
影响因子：
4.6
通讯作者：
Rosenblum, Norman D.
中科院分区：
文献类型：
--
作者：
Di Giovanni, Valeria;Alday, Adrian;Rosenblum, Norman D.
哺乳动物的肾脏和雄性生殖系统都起源于中间中胚层。骨形态发生蛋白（BMP）2和BMP 4及其同源受体激活素样激酶3（ALK 3）的时空表达表明，在中间中胚层衍生器官的形成过程中，BMP-ALK 3信号传导具有功能性作用。在这里，我们定义了细胞自主功能的Alk 3在肾脏和雄性性腺的小鼠与CRE-mediated Alk 3失活靶向中间中胚层祖细胞（Alk 3（IMP）（空））。Alk 3缺陷小鼠表现出简单的肾发育不全，其特征在于肾脏大小和肾单位数量减少，但组织结构正常。这些缺陷之前的Alk 3-删除细胞的后肾胚基和Osr 1和SIX 2，这标志着肾单位祖细胞的表达减少的贡献。突变小鼠的特征还在于中间中胚层衍生的生殖组织缺陷，中肾小管和睾丸间质细胞较少，出生后附睾体上皮空泡化，血清睾酮水平降低和生育力降低。ALK 3依赖性信号效应物的分析揭示了后肾间充质中磷酸化p38 MAPK和睾丸中磷酸化SMAD 1/5/8的谱系特异性减少。总之，这些结果证明在源自中间中胚层的不同祖细胞群体中需要Alk 3。
The mammalian kidney and male reproductive system are both derived from the intermediate mesoderm. The spatial and temporal expression of bone morphogenetic protein (BMP) 2 and BMP4 and their cognate receptor, activin like kinase 3 (ALK3), suggests a functional role for BMP-ALK3 signaling during formation of intermediate mesoderm-derivative organs. Here, we define cell autonomous functions for Alk3 in the kidney and male gonad in mice with CRE-mediated Alk3 inactivation targeted to intermediate mesoderm progenitors (Alk3(IMP) (null)). Alk3-deficient mice exhibit simple renal hypoplasia characterized by decreases in both kidney size and nephron number but normal tissue architecture. These defects are preceded by a decreased contribution of Alk3-deleted cells to the metanephric blastema and reduced expression of Osr1 and SIX2, which mark nephron progenitor cells. Mutant mice are also characterized by defects in intermediate mesoderm-derived genital tissues with fewer mesonephric tubules and testicular Leydig cells, epithelial vacuolization in the postnatal corpus epididymis, and decreased serum testosterone levels and reduced fertility. Analysis of ALK3-dependent signaling effectors revealed lineage-specific reduction of phospho-p38 MAPK in metanephric mesenchyme and phospho-SMAD1/5/8 in the testis. Together, these results demonstrate a requirement for Alk3 in distinct progenitor cell populations derived from the intermediate mesoderm.