Differential regulation of two sets of mesonephric tubules by WT-1

Mammalian renal development undergoes two transient stages, the pronephros and the mesonephros. While the regulation of metanephric differentiation has received considerable attention, very little is known about the mode of differentiation of the mesonephros and its regulation. We have followed mesonephric differentiation to unravel the developmental mechanisms and fates of mesonephric tubules by whole-mount immunohistology using antibodies to laminin, brush border epitopes, cytokeratin-8/18, p75 neurotrophin receptor and some other renal antigens as markers. In rat and mouse embryos, two distinct sets of tubules were observed throughout mesonephric development. Four to six pairs of cranial mesonephric tubules developed as outgrowths from the Wolffian duct. The majority of tubules were caudal tubules which never fused with the Wolffian and differentiated similarly to metanephric nephrons. The murine mesonephric tubules degenerate by apoptosis, except in males where the cranial tubules become the epididymal ducts. These developmental differences between the cranial and caudal sets of tubules suggested different regulatory systems for each. Targeted disruption of the Wilms' tumour gene product, WT-1, results in renal aplasia, and a reduction in the number of mesonephric tubules (Kreidberg, J. A., Sariola, H., Loring, J., Maeda, M., Pelletier, J., Housman, D. and Jaenisch, R. (1993). Cell 74, 679-691). We therefore analysed more closely mesonephric differentiation in WT-1-deficient mice, and showed that they only develop the cranial mesonephric tubules but not the caudal ones. Thus, WT-1 appears to regulate only the development of the caudal mesonephric tubules that conceivably are formed from mesenchymal cells like the metanephric tubules. WT-1 therefore seems to be necessary for the mesenchyme to epithelium transitions at different stages of nephrogenesis.