Abstract
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.
Highlights
Metanephric kidney development initiates at approximately E10.5 in mice, when the metanephric mesenchyme condenses at the posterior end of the nephrogenic cord adjacent to the hindlimbs
While the expression patterns of both Hox10 and Hox11 are largely overlapping, we observe that the anterior boundary of Hox10 expression in the nephrogenic cord is anterior to that of Hox11. Both Hox10 and Hox11 are expressed in the nephrogenic mesenchyme at E13.5, we find that Hox10 exhibits additional expression in the cortical stromal cells and suggests that these genes may be playing a unique role in the stroma
While a previous study has shown that Hox10 triple mutants develop severe skeletal defects [45], the potential role(s) these genes play in kidney organogenesis has not been reported
Summary
Metanephric kidney development initiates at approximately E10.5 in mice, when the metanephric mesenchyme condenses at the posterior end of the nephrogenic cord adjacent to the hindlimbs. These cells signal to the Wolffian duct to promote evagination of the ureteric bud, which invades the metanephric mesenchyme. After UB invasion, a number of transcription factors including Pax, Eya, Wt1, Sall, and the Hox are necessary to maintain Gdnf expression in the mesenchyme, promote continued proliferation and expansion of the mesenchyme and to control the further budding and branching of the epithelial ureteric tree [15,16,17,18,19,20,21,22,23].
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