Fox genes in urinary tract development

描述（由申请人提供）：肾脏和泌尿道的遗传性疾病在人类中相当常见，但其病因和潜在的发育机制知之甚少。很明显，动物模型需要进行表征，以阐明先天性尿路梗阻的分子和细胞机制。突变小鼠提供了有用的模型，以解决许多尚未解决的问题，先天性尿路梗阻，最近的研究表明，胚胎步骤的损害，输尿管出芽和分化的平滑肌周围输尿管，导致尿路异常，如输尿管积水和肾盂积水。Foxc 1和Foxc 2编码叉头/Fox转录因子，其具有几乎相同的DNA结合结构域和在各种胚胎组织中的重叠表达模式，包括中间中胚层、后肾间充质和输尿管周围的平滑肌祖细胞。我们先前已经表明，根据遗传背景，大多数Foxc 1纯合子突变体出生时具有后肾异常，包括双肾和双输尿管，其中之一是输尿管积水。最重要的是，Foxc 1纯合子有一个异位的输尿管前芽。这些发现支持了Mackie和Stephens关于先天性肾脏异常的人类婴儿中重复肾和输尿管积水的病因学的假设。有趣的是，大多数复合Foxc 1，Foxc 2杂合子有发育不良的肾脏和一个单一的输尿管积水，虽然他们有双输尿管芽，这表明这两个基因在肾脏和尿路发育功能相互作用。Foxd 2（另一个相关的Fox基因）的表达与发育中的肾脏和尿路中的Foxc 1和Foxc 2的表达重叠。我们还发现，Foxd 2突变小鼠有类似的缺陷，如输尿管积水，最近的分析化合物Foxc 1; Foxd 2纯合子揭示了输尿管形态发生的两个基因之间的功能重叠。所有这些工作的结果导致中心假设，即三个Fox转录因子在输尿管出芽和输尿管周围平滑肌分化的步骤中发挥协同作用。这一假设将通过以下方式进行检验：（1）分析三种Fox蛋白（Foxc 1、Foxc 2和Foxd 2）中的功能结构域，（2）分析复合Fox突变胚胎中输尿管芽的形成和生长，（3）分析复合Fox突变胚胎中输尿管周围平滑肌的发育。这些研究将大大有助于更好地了解婴儿和儿童先天性尿路梗阻的病因，并深入了解人类异常的细胞和分子基础。

DESCRIPTION (provided by applicant): Inherited disorders of the kidney and urinary tract are quite common in humans, but their etiology and underlying developmental mechanisms are poorly understood. It is clear that animal models need to be characterized to elucidate the molecular and cellular mechanisms of congenital obstruction of the urinary tract. Mutant mice provide useful models to address the many unresolved questions about congenital urinary tract obstruction, and recent studies have suggested that the impairment of embryonic steps, the ureteric budding and differentiation of smooth muscle around the ureter, leads to urinary tract abnormalities such as hydroureter and hydronephrosis. Foxc1 and Foxc2 encode forkhead/Fox transcription factors with virtually identical DNA binding domains and overlapping expression patterns in various embryonic tissues, including the intermediate mesoderm, metanephric mesenchyme, and smooth muscle progenitors surrounding the ureter. We have previously shown that depending on the genetic background most Foxc1 homozygous mutants are born with abnormalities of he metanephric kidney, including duplex kidneys, and double ureters, one of which is hydroureter. Most importantly, Foxc1 homozygotes have an ectopic anterior ureteric bud. These findings support the hypothesis of Mackie and Stephens concerning the etiology of duplex kidney and hydroureter in human infants with congenital kidney abnormalities. Interestingly, most compound Foxc1; Foxc2 heterozygotes have hypoplastic kidneys and a single hydroureter although they have double ureteric buds, suggesting that the two genes functionally interact in kidney and urinary tract development. Expression of Foxd2, another related Fox gene, overlaps with that of Foxc1 and Foxc2 in the developing kidney and urinary tract. We have also shown that Foxd2 mutant mice have similar defects such as hydroureter, and recent analysis of compound Foxc1; Foxd2 ihomozygotes revealed a functional overlap between the two genes in ureter morphogenesis. The results of all of this work lead to the central hypothesis that three Fox transcription factors play cooperative roles in the steps of the ureteric budding and smooth muscle differentiation surrounding the ureter. This hypothesis will be tested by: (1) analysis of functional domains in three Fox protein's (Foxc1, Foxc2, and Foxd2), (2) analysis of the formation and growth of the ureteric bud in compound Fox mutant embryos, (3) analysis of the development of smooth muscle surrounding the ureter in compound Fox mutant embryos. These studies will significantly contribute to a better understanding of the etiology of congenital urinary tract obstruction in infants and children and gain insight into the cellular and molecular basis of human abnormalities.