The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes
The podocyte-specific inactivation of Lmx1b, Ldb1 and E2a yields new insight into a transcriptional network in podocytes
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DOI：
10.1016/j.ydbio.2007.01.020
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发表时间：
2007-04-15
影响因子：
2.7
通讯作者：
Witzgall, Ralph
中科院分区：
文献类型：
--
作者：
Suleiman, Ham;Heudobler, Daniel;Witzgall, Ralph
患有指甲-髌骨综合征的患者，除其他症状外，还包括足细胞相关的肾衰竭，患有LMX 1B基因突变。患者之间的疾病严重程度是相当可变的，并引起了对修饰基因存在的猜测。有希望的候选修饰蛋白是与LMX 1B相互作用的蛋白质，如LDB 1和E47。由于很难获得患者的肾脏样本，因此常规的Lmx 1b基因敲除小鼠对于研究Lmx 1b在足细胞分化中的作用非常有价值。然而，与这些小鼠中的发现相反，其中已经描述了Col 4a 3、Col 4a 4和Nphs 2基因的下调，在患者的肾活检中没有检测到这样的变化。我们现在报告我们的组成型足细胞特异性Lmx 1b，Ldb 1和E2 a基因敲除小鼠的表征结果。组成型足细胞特异性Lmx 1b敲除小鼠在出生后存活约2周，并且不存在Col 4a 3、Col 4a 4和Nphs 2基因的下调，因此它们更接近于模拟人类疾病。足细胞特异性Ldb 1基因敲除小鼠存活时间更长，但随后也死于肾衰竭，而E2 a基因敲除小鼠在出生后至少6个月内没有表现出肾脏症状。我们的结论是LDB 1，而不是E2 A是一个有前途的候选人作为一个修饰基因在患者的指甲-髌骨综合征。(c)2007年爱思唯尔公司All rights reserved.
Patients with nail-patella syndrome, which among other symptoms also includes podocyte-associated renal failure, suffer from mutations in the LMX1B gene. The disease severity among patients is quite variable and has given rise to speculations on the presence of modifier genes. Promising candidates for modifier proteins are the proteins interacting with LMX1B, such as LDB1 and E47. Since human kidney samples from patients are difficult to obtain, conventional Lmx1b knock-out mice have been extremely valuable to study the role of Lmx1b in podocyte differentiation. In contrast to findings in these mice, however, in which a downregulation of the Col4a3, Col4a4 and Nphs2 genes has been described, no such changes have been detected in kidney biopsies from patients. We now report on our results on the characterization of constitutive podocyte-specific Lmx1b, Ldb1 and E2a knock-out mice. Constitutive podocyte-specific Lmx1b knock-out mice survive for approximately 2 weeks after birth and do not present with a downregulation of the Col4a3, Col4a4 and Nphs2 genes, therefore they mimic the human disease more closely. The podocyte-specific Ldb1 knock-out mice survive longer, but then also succumb to renal failure, whereas the E2a knock-out mice show no renal symptoms for at least 6 months after birth. We conclude that LDB1, but not E2A is a promising candidate as a modifier gene in patients with nail-patella syndrome. (c) 2007 Elsevier Inc. All rights reserved.