IFT25 Links the Signal-Dependent Movement of Hedgehog Components to Intraflagellar Transport

Abstract

The intraflagellar transport (IFT) system is required for building primary cilia, sensory organelles that cells use to respond to their environment. IFT particles are composed of about 20 proteins and these proteins are highly conserved across ciliated species. IFT25, however, is absent from some ciliated organisms suggesting it may have a unique role distinct from ciliogenesis. Here, we generate an Ift25 null mouse and show that IFT25 is not required for ciliary assembly but is required for proper Hedgehog signaling, which in mammals occurs within cilia. Mutant mice die at birth with multiple phenotypes indicative of Hedgehog signaling dysfunction. Cilia lacking IFT25 have defects in the signal-dependent transport of multiple Hedgehog components including Patched-1, Smoothened, and Gli2 and fail to activate the pathway upon stimulation. Thus, IFT function is not restricted to building cilia where signaling occurs, but also plays a separable role in signal transduction events.

The loss of Hh responsiveness by a non-ciliary Gli2 variant

“…In one such study, the disruption of the cytoplasmic microtubule network through a drug treatment abolished the ciliary localization of Gli2 and disrupted the Hh signaling (Kim et al, 2009). Similarly, mutations in a microtubule motor protein Kif7, or in an intraflagellar transport protein Ift25, affected Gli2 ciliary localization and Hh pathway activation (Cheung et al, 2009;Endoh-Yamagami et al, 2009;He et al, 2014;Keady et al, 2012;Liem et al, 2009). One major concern with this approach is that additional proteins and processes affected by the disruption of cytoskeleton or transport machinery may contribute to the observed disruption of Hh signaling.…”

“…All mammalian Gli proteins, as well as Sufu, localize to the tip of the cilium in a coordinated process, which is further enhanced by Hh signaling Haycraft et al, 2005;Wen et al, 2010;Zeng et al, 2010b). Disturbing the cytoplasmic microtubule network or intraflagellar transport (IFT) has been shown to reduce Gli2 ciliary localization and coincidently disrupt Hh signaling (Keady et al, 2012;Kim et al, 2009). However, as cytoskeleton and IFT affect the localization of numerous other cellular components, these approaches have not adequately established a connection between Gli2 ciliary localization and Hh pathway activation.…”

Cilia and coordination of signaling networks during heart development

“…21,166 Finally, defects in proper trafficking of Smo and Ptch1 in and out of the cilium due to mutations in Ift25 lead to cardiac phenotypes in mice reminiscent of those found in Hh signaling mutants, including defects involving the ventricle, OFT and AVC. 154 …”

“…4), 21,22,142 and defective ciliary assembly is associated with defective cardiomyogenesis 21 as well as Hh-related heart defects that might be independent of nodal cilia, including ventricular and endocardial cushion-derived defects. 122,142,154 Further, 60% of patients with mutations in genes encoding the EVC proteins, EVC1/EVC2, which interact with Smo at the primary cilium to transduce Hh signaling [155][156][157][158][159] , display CHD, including AVSD and ASD. 47,51 In line with these findings, EVC proteins are coexpressed in the OFT and the mesenchymal structures of the atrial septa and AV cushions during heart development in mice 51 ; areas that are known to be ciliated during cardiogenesis.…”

Cils et morphogenèse cardiaque

“…C'est le cas chez les mutants hypomorphes Ift88 cbs/cbs , qui reproduisent les défauts d'une faible signalisation Shh [32]. La signalisation Shh est modulée par d'autres composants de la machinerie de transport ciliaire, tels que Ift25 [33], qui sont ainsi requis pour le cloisonnement du coeur. Chez l'homme, de tels défauts sont observés dans le syndrome ciliopathique Ellis van Creveld (EVC).…”