FGF8 is required for cell survival at distinct stages of nephrogenesis and for regulation of gene expression in nascent nephrons

Abstract

During kidney morphogenesis, the formation of nephrons begins when mesenchymal nephron progenitor cells aggregate and transform into epithelial vesicles that elongate and assume an S-shape. Cells in different regions of the S-shaped body subsequently differentiate into the morphologically and functionally distinct segments of the mature nephron. Here, we have used an allelic series of mutations to determine the role of the secreted signaling molecule FGF8 in nephrogenesis. In the absence of FGF8 signaling, nephron formation is initiated, but the nascent nephrons do not express Wnt4or Lim1, and nephrogenesis does not progress to the S-shaped body stage. Furthermore, the nephron progenitor cells that reside in the peripheral zone, the outermost region of the developing kidney, are progressively lost. When FGF8 signaling is severely reduced rather than eliminated, mesenchymal cells differentiate into S-shaped bodies. However, the cells within these structures that normally differentiate into the tubular segments of the mature nephron undergo apoptosis, resulting in the formation of kidneys with severely truncated nephrons consisting of renal corpuscles connected to collecting ducts by an abnormally short tubular segment. Thus, unlike other FGF family members, which regulate growth and branching morphogenesis of the collecting duct system, Fgf8 encodes a factor essential for gene regulation and cell survival at distinct steps in nephrogenesis.

Transcriptional profiling of Wnt4 mutant mouse kidneys identifies genes expressed during nephron formation

“…Studies of several signaling pathways, as well as transcription factors, have revealed genes involved in the patterning the nephron including Fgf8 (Grieshammer et al, 2005), Pou3f3 (Nakai et al, 2003),Sprouty (Basson et al, 2005;Basson et al, 2006), Notch/presenillins (Cheng et al, 2007;Cheng et al, 2003;McCright et al, 2002), and Lhx1 (Kobayashi et al, 2005). In particular, genetic studies have shown several members of the Wnt family of lipidmodified secreted glycoproteins have important roles in the initiation and maintenance of nephron formation and branching morphogenesis Kispert et al, 1998;Majumdar et al, 2003;Stark et al, 1994).…”

“…Some genes failed to meet the statistical cutoff though they are expressed in E14.5 kidney. These included Fgf8 (Grieshammer et al, 2005), ret (Pachnis et al, 1993;Schuchardt et al, 1994), Pou3f3 (Nakai et al, 2003), Wnt7b (Kispert et al, 1996;Patterson et al, 2001), Ihh (Valentini et al, 1997), and Shh (Yu et al, 2002). Overall, the wildtype profiles had 6824 Present calls (54.9%) and the Wnt4 mutant profiles had 6628 Present calls (53.4%).…”

The prepattern transcription factor Irx3 directs nephron segment identity

“…Furthermore, specification of proximal lineages also requires Lim1/Lhx1 gene function (Kobayashi et al 2005), which may act as an upstream regulator of Notch signaling. Finally, survival of proximal tubular fates is dependent on FGF8 (Grieshammer et al 2005). Far less is known how the more distal nephron segments are specified.…”

Identification of Novel Wilms' Tumor Suppressor Gene Target Genes Implicated in Kidney Development

“…The importance of FGF signaling in kidneys has been demonstrated using a transgenic mouse expressing dominant negative FGF receptor (57). The expression of FGF-1 and FGF receptor 1 can be detected in the metanephric mesenchyme during early renal development (58,59), and FGF-1 stimulates ureteric bud branching in organ culture (60). Our study has also identified a number of signaling molecules as WT1 targets, such as IL1RAP, GRB10, SH3-BP5, and other membrane and signaling proteins (supplemental Table S3), that could potentially play important roles to autocrine or paracrine signaling from the ureteric bud for mesenchymal cell survival and differentiation.…”