Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development

Abstract

Eukaryotic cilia are assembled by intraflagellar transport (IFT) where large protein complexes called IFT particles move ciliary components from the cell body to the cilium. Defects in most IFT particle proteins disrupt ciliary assembly and cause mid gestational lethality in the mouse. IFT25 and IFT27 are unusual components of IFT-B in that they are not required for ciliary assembly and mutant mice survive to term. The mutants die shortly after birth with numerous organ defects including duplex kidneys. Completely duplex kidneys result from defects in ureteric bud formation at the earliest steps of metanephric kidney development. Ureteric bud initiation is a highly regulated process involving reciprocal signaling between the ureteric epithelium and the overlying metanephric mesenchyme with regulation by the peri-Wolffian duct stroma. The finding of duplex kidney in Ift25 and Ift27 mutants suggests functions for these genes in regulation of ureteric bud initiation. Typically the deletion of IFT genes in the kidney causes rapid cyst growth in the early postnatal period. In contrast, the loss of Ift25 results in smaller kidneys, which show only mild tubule dilations that become apparent in adulthood. The smaller kidneys appear to result from reduced branching in the developing metanephric kidney. This work indicates that IFT25 and IFT27 are important players in the early development of the kidney and suggest that duplex kidney is part of the ciliopathy spectrum.

Rabl2 GTP hydrolysis licenses BBSome‐mediated export to fine‐tune ciliary signaling

“…Notably, the neonatal lethality, duplex kidney, normal ciliation, and ciliary accumulation of BBSome and GPCRs are also characteristic phenotypes of the Ift27 null mice (Eguether et al , 2014; Desai et al , 2018). Ift27 is a Rab‐like small GTPase (also termed Rabl4) stabilized by Ift25 through heterodimerization and also the essential subunit for the coupling of IFT‐B to the BBSome and its cargos (Fig 7H) (Bhogaraju et al , 2011; Keady et al , 2012; Eguether et al , 2014; Blacque et al , 2018; Nakayama & Katoh, 2018).…”

“…The largely shared phenotypes between our Rabl2 KI/KI mice (Fig 7A -G) and the Ift27-deficient mice (Eguether et al, 2014;Desai et al, 2018) appear to indicate that the ciliary Rabl2-GTP functions to counteract or repress Ift27 on IFT-B. Unlike many other IFT-B core subunits, mammalian Ift27 and Ift25 are dispensable for anterograde IFT, ciliogenesis, and early embryo viability.…”

“…As both the Rabl2 deficiency and Rabl2 Q80L expression impaired Hh signaling (Figs 2 and 3 and 7), a proper balance between the TZ export and the ciliary retention of Smo and Gpr161 is critical for optimal Hh signaling (Fig 7H). Accordingly, the polydactyly of Rabl2 ‐deficient mice (Fig EV1A and B) (Kanie et al , 2017) and the neonatal lethality and duplex kidney of the Rabl2 KI / KI mice (Fig 7C and D) may result from aberrant Hh signaling (Eguether et al , 2014; Tickle & Towers, 2017; Desai et al , 2018; D'Cruz et al , 2020). The retina degeneration, obesity, and male infertility of the Rabl2 ‐deficient mice (Fig EV1C–G) (Kanie et al , 2017) and Rabl2 Mot / Mot mice (Lo et al , 2012; Lo et al , 2016), whose etiology could be attributed to premature dissociation of ciliary Rabl2 D73G ‐GTP from IFT‐B according to our results (Fig 6) to partly resemble Rabl2 deficiency, also implicate abnormal ciliary signaling of other GPCRs (Forsythe & Beales, 2013; Hilgendorf et al , 2016).…”

“…Ift27 is a Rab-like small GTPase (also termed Rabl4) stabilized by Ift25 through heterodimerization and also the essential subunit for the coupling of IFT-B to the BBSome and its cargos (Fig 7H) (Bhogaraju et al, 2011;Keady et al, 2012;Eguether et al, 2014;Blacque et al, 2018;Nakayama & Katoh, 2018). Ift25-deficient mice also show similar phenotypes except for the less extent of neonatal death (Keady et al, 2012;Desai et al, 2018). Therefore, the Rabl2 Q80L expression is largely equivalent to the depletion of Ift27.…”

Duplex kidney formation: developmental mechanisms and genetic predisposition

“…A number of other genes involved in duplex kidney formation appear to affect the BMP/Gremlin axis. Mutants for the intraflagellar transport proteins IFT25 or IFT27, which are believed to increase GLI3R, a repressor of SHH signalling, show a high penetrance of duplex kidney formation (~50%) 84 . Similarly, constitutive expression of a truncation mutation in Gli3 (Gli3 Δ699 ), which is found in Pallister-Hall syndrome and is likely to sensitise tissue for SHH signalling, causes CAKUT with duplex kidneys 85 .…”