Background and question:

The recently discovered ADAMTS16 molecule (a disintegrin and metalloproteinase with thrombospondin motifs) is a secreted metalloproteinase with unknown function. Based on structural similarity with other ADAMTS members one would predict a role for ADAMTS16 in extracellular matrix degradation. The purpose of this study was to explore the tissue distribution of ADAMTS16 and to identify possible trans-regulatory factors involved in its expression.

Methods and results:

Using immunohistochemistry we detected Adamts16 protein in the developing genitourinary system of mouse embryos. Adamts16 was co-expressed with the Wilms’ tumor protein, Wt1, in glomerular precursors of embryonic murine kidneys and in podocytes of mature glomeruli. Knockdown of the Wt1 transcription factor significantly reduced Adamts16 mRNA levels in fetal kidney explants and in a mesonephric cell line. Several predicted Wt1 consensus motifs could be identified in the promoter and the 5’-untranslated region of the murine Adamts16 gene. Binding of Wt1 protein to these elements was verified by electrophoretic mobility shift experiments and chromatin immunoprecipitation (ChIP). A firefly luciferase reporter gene under control of the Adamts16 promoter was activated approximately 8-fold by transient co-transfection of a Wt1 expression construct. Transfection with Adamts16 antisense vivo-morpholino severely impaired the in vitro differentiation of cultured murine fetal kidneys.

Conclusions:

These findings demonstrate that transcription of the Adamts16 gene is stimulated by Wt1. It is further suggested that Adamts16 has a pivotal role in kidney morphogenesis.