FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling

Abstract

Highlights d Fat4 mutant mice have duplex kidney defects due to ectopic bud formation d FAT4 functions non-autonomously in the mesenchyme to prevent kidney duplication d RET signaling is overactive in Fat4 mutants d FAT4 interacts with RET, perturbs RET-GFRA1-GDNF assembly, and reduces RET signaling

Embryonic Kidney Development, Stem Cells and the Origin of Wilms Tumor

“…Orchestrated repetition of this cycle in a highly regulated manner ensures the maintenance of all relevant cell types until the completion of kidney organogenesis. Renal stroma is a part of the mesenchymal population that caps the nephron-forming mesenchyme and is critical not only for the formation of mesangial cells and interstitium, but also actively participates in the regulation of branching morphogenesis, and the proper differentiation of nephrons and vasculature [ 19 , 20 , 21 , 22 , 23 , 24 ]. While the innervation and vascular network formation are essential features of functional kidney development and recent studies indicate a presence of endothelial precursors in embryonic kidney, these topics are not discussed here (for insights, see [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]).…”

“…Other data suggests FAT4 might signal via DCHS1 rather than YAP/TAZ, as the conditional knockout of Dchs1 in the nephron progenitors resulted in a comparable enlargement of the cap mesenchyme, but interestingly also in the reduced branching of the ureteric bud [ 110 , 111 ]. These branching phenotypes are mediated through the direct interaction of FAT4 and DCHS1 with RET, with Fat4 loss resulting in an overactive RET-GFRA1-GDNF cascade [ 21 ]. Finally, the Foxd1-Cre-mediated loss of Sall1 in the stromal compartment results in expanded cap mesenchyme, potentially through direct control of Fat4 expression by SALL1 [ 112 ]; in this case, effects on the ureteric bud were not studied.…”

The Biological Significance and Implications of Planar Cell Polarity for Nephrology

“…Ureteric bud branching defects in mouse are also observed upon deletion of Fat4 (Mao et al, 2011(Mao et al, , 2015 and Dchs1 (Mao et al, 2011;Bagherie-Lachidan et al, 2015); mammalian homologues for Ft and Ds, respectively. However, the precise role of FAT4 and DCHS1 in ureteric bud branching is not yet clear, as neither protein is localised to the ureteric bud (Mao et al, 2011(Mao et al, , 2015Bagherie-Lachidan et al, 2015) and these models exhibit other renal anomalies such as duplex kidney and alterations of GDNF signalling (Mao et al, 2011(Mao et al, , 2015Bagherie-Lachidan et al, 2015;Zhang et al, 2019).…”

Kidneys Prefer a High Fat4 Diet

“…Remarkably, Zhang et al now show that Fat4 and Ret control stroma-epithelial signaling via direct interaction of their respective cadherin repeats, which are closely related, and they show that these interactions are critical for restricting ureteric budding and branching to a single site at the caudal aspect of the nephric duct. The results of Zhang et al (2019) provide a new model of stromal-ureteric bud signaling (Figure 1), regulated by Fat4 and Ret, that is critical for urinary tract formation and provide a signaling pathway that is important for modulating stereotypical ureteric bud outgrowth, an event that is central to urinary tract function. It will be interesting to determine whether Fat4 mutations are also present in other syndromes characterized by lower urinary tract defects and whether these mutations affect Fat4's ability to interact with Ret.…”

“…The presence of duplicated ureters in Fat4 mutants suggests that Fat4 signaling normally plays a role in controlling ureteric bud outgrowth or branching; however, the mechanism by which Fat4 regulates these events is unclear. In the current issue of Developmental Cell, Zhang et al (2019) characterize urinary tract phenotypes in Fat4 mutant embryos. Mutants lacking Fat4 and Fjx1, a transmembrane protein that interacts with Fat4, displayed a low incidence of duplicated ureters that increased substantially when the mutations were backcrossed onto a C57BL/6J background, compared to mice of CD1 or 129S1 backgrounds, indicating an influence of variable genetic enhancers on kidney duplication.…”