Canonical Wnt9b signaling balances progenitor cell expansion and differentiation during kidney development

Abstract

SUMMARYThe mammalian kidney is composed of thousands of individual epithelial tubules known as nephrons. Deficits in nephron number are associated with myriad diseases ranging from complete organ failure to congenital hypertension. A balance between differentiation and maintenance of a mesenchymal progenitor cell population determines the final number of nephrons. How this balance is struck is poorly understood. Previous studies have suggested that Wnt9b/-catenin signaling induced differentiation (mesenchymal-to-epithelial transition) in a subset of the progenitors but needed to be repressed in the remaining progenitors to keep them in the undifferentiated state. Here, we report that Wnt9b/-catenin signaling is active in the progenitors and is required for their renewal/proliferation. Using a combination of approaches, we have revealed a mechanism through which cells receiving the same Wnt9b/-catenin signal can respond in distinct ways (proliferate versus differentiate) depending on the cellular environment in which the signal is received. Interpretation of the signal is dependent, at least in part, on the activity of the transcription factor Six2. Six2-positive cells that receive the Wnt9b signal are maintained as progenitors whereas cells with reduced levels of Six2 are induced to differentiate by Wnt9b. Using this simple mechanism, the kidney is able to balance progenitor cell expansion and differentiation insuring proper nephron endowment. These findings provide novel insights into the molecular mechanisms that regulate progenitor cell differentiation during normal and pathological conditions.

In situ histone landscape of nephrogenesis

“…12 Uninduced nephron progenitors express "stemness" genes such as Six2 but are also poised to undergo mesenchymeto-epithelium transition in response to inductive Wnt signaling emanating from the adjacent UB. [13][14][15] In this regard, Six2 interacts and cooperates with Lef/Tcf factors and β-catenin to initiate expression of nephrogenic genes such as Wnt4, Lhx1, Pax8, and Fgf8. We recently examined the chromatin landscape in MM cell lines using ChIP-Seq and reported that whereas H3K4me3 peaks predominantly decorate metabolic genes, H3K27me3 peaks are highly specific to developmental genes in each cell line.…”

Histone Deacetylase (HDAC) Activity Is Critical for Embryonic Kidney Gene Expression, Growth, and Differentiation

“…Release of Wnt9b from the UB branches triggers a ␤-catenindependent morphogenetic program leading to expression of Wnt4, Fgf8, and Pax8 and transition of ventrally located MM cells to epithelial nephron progenitors (pretubular aggregates and renal vesicles) (23,24). Wnt9b signaling cooperates with Six2, a transcription factor expressed exclusively in the dorsal metanephric cap region to maintain the proliferation or selfrenewal of pluripotent MM cells (25)(26)(27). Subsequently, the Lim homeodomain transcription factor, Lhx1 (also known as Lim-1), a downstream target of Wnt4/Fgf8 signaling, mediates further maturation to comma-and S-shaped bodies (28 -30).…”

Defining the Signals that Constitute the Nephron Progenitor Niche

“…21 Although the nephron progenitor population is initially present and specified correctly in Wnt9b mutants, it shows a very low proliferation rate relative to wildtype. 22 Treatment of isolated mesenchyme with Wnt9b leads to expansion and maintenance of the nephron progenitors alongside the MET, suggesting that Wnt9b also promotes proliferation. This could be a direct role for Wnt9b on the progenitors or an indirect role resulting from Wnt9b's ability to induce renal vesicles.…”