Six2 is required for suppression of nephrogenesis and progenitor renewal in the developing kidney

Abstract

During kidney development and in response to inductive signals, the metanephric mesenchyme aggregates, becomes polarized, and generates much of the epithelia of the nephron. As such, the metanephric mesenchyme is a renal progenitor cell population that must be replenished as epithelial derivatives are continuously generated. The molecular mechanisms that maintain the undifferentiated state of the metanephric mesenchymal precursor cells have not yet been identified. In this paper, we report that functional inactivation of the homeobox gene Six2 results in premature and ectopic differentiation of mesenchymal cells into epithelia and depletion of the progenitor cell population within the metanephric mesenchyme. Failure to renew the mesenchymal cells results in severe renal hypoplasia. Gain of Six2 function in cortical metanephric mesenchymal cells was sufficient to prevent their epithelial differentiation in an organ culture assay. We propose that in the developing kidney, Six2 activity is required for maintaining the mesenchymal progenitor population in an undifferentiated state by opposing the inductive signals emanating from the ureteric bud.

Stem cell options for kidney disease

“…While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only.…”

“…This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2].…”

“…There are numerous transcription factors implicated in the specification of the mesenchyme progenitor population in the developing kidney [123]. Individual inactivation of Wt1 [124], Pax2 [125], Eya1 [126], Six1 [127], Six2 [5], Osr1 [128] and Sall1 [129] all result in renal agenesis. As noted previously, the Six2 knockout phenotype exhibits ectopic epithelialization and depletion of the CM, demonstrating that Six2 is absolutely required for the renewal of the cap mesenchyme population [5].…”

“…Individual inactivation of Wt1 [124], Pax2 [125], Eya1 [126], Six1 [127], Six2 [5], Osr1 [128] and Sall1 [129] all result in renal agenesis. As noted previously, the Six2 knockout phenotype exhibits ectopic epithelialization and depletion of the CM, demonstrating that Six2 is absolutely required for the renewal of the cap mesenchyme population [5]. With the recent generation of Six2GFPCre mice [12], it is likely that additional specifiers of the CM fate will be discovered that may represent additional reprogramming factors.…”

A spatially-averaged mathematical model of kidney branching morphogenesis

“…One may predict that if survival or proliferation of either the mesenchyme or the epithelium were suppressed, this might retard, or even terminate, development. Certainly, a global switch for the mesenchyme to differentiate rather than proliferate (self-renew) completely represses subsequent branching (Self et al, 2006). Conversely, some genetic examples of hypoplasia, with an overall reduction in ureteric branching, show evidence for a reduction in ureteric epithelial proliferation (Cain and Rosenblum, 2011).…”