The Role of Cited Family Proteins in the Developing Kidney

Abstract

Kidney development in mammals is characterized by reciprocal tissue interaction between the ureteric bud and the metanephric mesenchyme. The outgrowing epithelial bud invades the overlying mesenchyme, inducing epithelial differentiation of these renal progenitor cells. In turn, signals from the metanephric mesenchyme allow for continued growth and branching of the ureteric bud, which will form the collecting system. This program is regulated largely at the transcriptional level and the co-factor Cited1 has been implicated in regulation of metanephric mesenchyme differentiation. Here we investigate the expression and function of Cited1 in the developing mouse kidney. Cited1 is expressed in the metanephric mesenchyme subsequent to ureteric bud invasion and is restricted to a subset of cells that aggregate tightly around the bud tip. This structure, known as the cap mesenchyme, contains renal progenitor cells and will undergo epithelial differentiation in response to signals from the ureteric bud. As this program is initiated, Cited1 is down regulated, and is absent in early epithelial structures. Despite its unique expression pattern, deletion of Cited1 does not disrupt kidney development. We hypothesized that this was due to redundancy through Cited2 and Cited4, other members of this gene family expressed in the developing kidney. Deletion of either Cited2 or Cited4 alone or in combination with Cited1 did not disrupt the ability of the metanephric mesenchyme to differentiate or the ureteric bud to branch. Though we have a general appreciation that the cap mesenchyme gives rise to nephrons, careful lineage analysis of this progenitor population has not been previously reported. By exploiting the unique expression domain of Cited1, we have generated a transgenic mouse that expresses an inducible Cre recombinase, allowing us to tag cap mesenchyme cells and follow their fate potential. These studies address the fate of the cap mesenchyme in vivo for the first time using a genetic system and define which cell types do and do not arise from this population. In addition, this line will be useful in a broader sense as a powerful tool for conditional gene deletion within the cap mesenchyme.