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Organogenesis requires the differentiation and integration of distinct populations of cells to form a functional organ. In the kidney, reciprocal interactions between the ureter and the nephrogenic mesenchyme are required for organ formation. Additionally, the differentiation and integration of stromal cells are also necessary for the proper development of this organ. Much remains to be understood regarding the origin of cortical stromal cells and the pathways involved in their formation and function. By generating triple mutants in the  Hox10  paralogous group genes, we demonstrate that  Hox10  genes play a critical role in the developing kidney. Careful examination of control kidneys show that  Foxd1- expressing stromal precursor cells are first observed in a cap-like pattern anterior to the metanephric mesenchyme and these cells subsequently integrate posteriorly into the kidney periphery as development proceeds. While the initial cap-like pattern of  Foxd1 -expressing cortical stromal cells is unaffected in  Hox10  mutants, these cells fail to become properly integrated into the kidney, and do not differentiate to form the kidney capsule. Consistent with loss of cortical stromal cell function,  Hox10  mutant kidneys display reduced and aberrant ureter branching, decreased nephrogenesis. These data therefore provide critical novel insights into the cellular and genetic mechanisms governing cortical cell development during kidney organogenesis. These results, combined with previous evidence demonstrating that  Hox11  genes are necessary for patterning the metanephric mesenchyme, support a model whereby distinct populations in the nephrogenic cord are regulated by unique  Hox  codes, and that differential  Hox  function along the AP axis of the nephrogenic cord is critical for the differentiation and integration of these cell types during kidney organogenesis.

Hox10 Genes Function in Kidney Development in the Differentiation and Integration of the Cortical Stroma