We previously established that the expression of the human nov gene (novH) was altered in Wilms'
tumors and that levels of novH and WT1
mRNA were inversely correlated in individual Wilms'
tumors. Insofar as novH has been shown to be a target for WT1 regulation, novH might play an important role during normal nephrogenesis and in the development of Wilms'
tumors. We now show that during normal nephrogenesis
novH protein is tightly associated with differentiation of glomerular podocytes. NovH expression is not restricted to renal differentiation but is also detected in endothelium and neural tissue of the kidney. Our results establish that alteration of novH expression in sporadic and heritable Wilms'
tumors is associated with dysregulated expression of both novH
mRNA and
protein. In general, the highest novH expression was noted in the
Wilms' tumor, genitourinary anomalies,
aniridia, and
mental retardation (WAGR)-associated Wilms'
tumors. Expression in the
Denys-Drash syndrome (DDS)-associated Wilms'
tumors fell within the variable spectrum observed in sporadic
Wilms' tumor cases. As in developing kidney podocytes,
novH protein was also prominent in the abnormal hypoplastic podocytes from DDS cases and in kidney podocytes adjoining Wilms'
tumors. In Wilms'
tumors exhibiting heterotypic differentiation,
novH protein was expressed at high levels in
tumor-derived striated muscle and at lower levels in
tumor-derived cartilage. These observations taken together indicate that novH may represent both a marker of podocytic differentiation in kidney and a marker of heterotypic mesenchymal differentiation in Wilms'
tumors. In addition, absence or very low levels of WT1 are correlated with higher novH expression, and its variable expression in cases with mutant WT1 (sporadic and DDS) suggests that the potential activation and repression transcriptional functions possessed by WT1 are likely dependent on the specific mutation incurred.