Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia
Loss of Bmp7 and Fgf8 signaling in Hoxa13-mutant mice causes hypospadia
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DOI：
10.1242/dev.00530
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发表时间：
2003-07-01
期刊：
影响因子：
4.6
通讯作者：
Stadler, HS
中科院分区：
文献类型：
--
作者：
Morgan, EA;Nguyen, SB;Stadler, HS
在人类和小鼠中，Hoxa13的突变会导致肢体和泌尿生殖器（GU）区域的畸形。在男性中，与Hoxa 13功能丧失相关的最常见GU畸形之一是尿道下裂，这是一种由尿道和阴茎头的生长和闭合不良定义的疾病。通过研究发育中小鼠生殖器结节的早期信号，我们发现Hoxa13对尿道板上皮中Fgf8和Bmp7的正常表达至关重要。在Hoxa13（GFP）突变小鼠中，尿道下裂的发生是由于尿道板上皮中Fgf8和Bmp7表达的联合丧失以及侧翼间充质中头蛋白（Nog）的异位表达。在体外补充Fgf8恢复纯合突变体的增殖野生型水平，这表明Fgf8足以指导发育中的生殖器结节的早期增殖。然而，远端尿道和龟头的闭合缺陷可归因于尿道中细胞凋亡的丧失，这与该区域中Bmp7表达的减少一致。Hoxa13突变小鼠也表现出雄激素受体表达的变化，提供了Hoxa13相关尿道下裂和雄激素信号拮抗剂产生的尿道下裂之间的发育联系。最后，Hoxa13在阴茎头血管化中的新作用也被确定。
In humans and mice, mutations in Hoxa13 cause malformation of limb and genitourinary (GU) regions. In males, one of the most common GU malformations associated with loss of Hoxa13 function is hypospadia, a condition defined by the poor growth and closure of the urethra and glans penis. By examining early signaling in the developing mouse genital tubercle, we show that Hoxa13 is essential for normal expression of Fgf8 and Bmp7 in the urethral plate epithelium. In Hoxa13(GFP)- mutant mice, hypospadias occur as a result of the combined loss of Fgf8 and Bmp7 expression in the urethral plate epithelium, as well as the ectopic expression of noggin (Nog) in the flanking mesenchyme. In vitro supplementation with Fgf8 restored proliferation in homozygous mutants to wild-type levels, suggesting that Fgf8 is sufficient to direct early proliferation of the developing genital tubercle. However, the closure defects of the distal urethra and glans can be attributed to a loss of apoptosis in the urethra, which is consistent with reduced Bmp7 expression in this region. Mice mutant for Hoxa13 also exhibit changes in androgen receptor expression, providing a developmental link between Hoxa13-associated hypospadias and those produced by antagonists to androgen signaling. Finally, a novel role for Hoxa13 in the vascularization of the glans penis is also identified.