Kidney Development in Cadherin-6 Mutants: Delayed Mesenchyme-to-Epithelial Conversion and Loss of Nephrons

Abstract

During nephrogenesis, dynamic changes in the expression of cell adhesion molecules are evident as epithelial structures differentiate from the induced mesenchyme. The cadherins are thought to play an important role in the metanephric mesenchyme, when cells aggregate to form the renal vesicle, a polarized epithelial structure which eventually fuses with the ureteric bud to generate a continuous nascent nephron. We have generated and analyzed mice with a targeted mutation in the gene encoding cadherin-6 (Cad-6), a type II cadherin expressed during early stages of nephrogenesis. These mice are viable and fertile, and they complete both early and late aspects of nephrogenesis. However, upon closer examination in vitro and in vivo, a fraction of the induced metanephric mesenchyme in Cad-6 mutant kidneys fails to form a fully polarized epithelium on schedule. Moreover, a significant number of the renal vesicles in Cad-6 mutant kidneys apparently fail to fuse to the ureteric bud. These alterations in epithelialization and fusion apparently lead to a loss of nephrons in the adult. These studies support the idea that cadherins play an essential role in the formation of epithelial structures and underscore the importance of timing in orchestrating the morphogenesis of complex epithelial tissues.

Cadherin-6 is required for zebrafish nephrogenesis during early development

“…We consider that abnormalities in filtration would be lethal in zebrafish, which have only a single nephron. Therefore, in contrast to CDH6-knockout mice (Mah et al, 2000), which are both viable and fertile, cdh6 is necessary for the normal development and survival of zebrafish. cdh6 and cdh17 seem to regulate development of the different parts of the pronephros during early embryogenesis During development, cdh6 and cdh17 are expressed in different regions of the pronephros, suggesting that these proteins have mutually supplementary roles in the morphogenesis of the pronephros.…”

“…There have been a number of studies of the expression and function of cadherin-6 (K-cadherin), a member of the classical type II cadherin subfamily (Redies, 1995), in normal renal development (Cho et al, 1998;Mah et al, 2000) and in the formation of renal carcinoma (Xiang et al, 1994). Cadherin-6 has also been shown to be expressed in the mouse, chicken and Xenopus nervous systems (Inoue et al, 1997;Nakagawa and Takeichi, 1998;David and Wedlich, 2000).…”

Expression of cadherin‐8 in renal cell carcinoma and fetal kidney

“…31 In mice with a targeted mutation in the gene encoding for cadherin-6, an alteration in epithelialization and fusion leading to loss of nephrons in adult mice has subsequently been detected. 32 E-cadherin has been detected in the collecting ducts, the upper limb of the S-shaped bodies and the distal tubules; but antibodies against it have failed to inhibit early kidney development. 33 In a study of the developmental expression of P-cadherin, it was first detected in the ureteric bud and tubuli as well as in vesicle stage glomeruli.…”

cadherin‐6 Message expression in the nervous system of developing zebrafish

“…Cadherin-6 (called K-cadherin previously) is a member of the type-II cadherin subfamily (Redies, 1995;Nollet et al, 2000). The majority of studies on cadherin-6 have focused on its expression and function in normal renal development and/or renal carcinoma formation (Xiang et al, 1994;Cho et al, 1998;Mah et al, 2000;Paul et al, 2004). Cadherin-6 expression in the nervous system has been analyzed in a variety of vertebrate species including Xenopus (David and Wedlich, 2000), chick (Nakagawa and Takeichi, 1995), and mouse (Inoue et al, 1997).…”