Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4

Abstract

Primary cilia are assembled and maintained by evolutionarily conserved intraflagellar transport (IFT) proteins that are involved in the coordinated movement of macromolecular cargo from the basal body to the cilium tip and back. The IFT machinery is organized in two structural complexes named complex A and complex B. Recently, inactivation in the mouse germline of Ift genes belonging to complex B revealed a requirement of ciliogenesis, or proteins involved in ciliogenesis, for Sonic Hedgehog (Shh) signaling in mammals. Here we report on a complex A mutant mouse, defective for the Ift122 gene. Ift122-null embryos show multiple developmental defects (exencephaly, situs viscerum inversus, delay in turning, hemorrhage and defects in limb development) that result in lethality. In the node, primary cilia were absent or malformed in homozygous mutant and heterozygous embryos, respectively. Impairment of the Shh pathway was apparent in both neural tube patterning (expansion of motoneurons and rostro-caudal level-dependent contraction or expansion of the dorso-lateral interneurons), and limb patterning (ectrosyndactyly). These phenotypes are distinct from both complex B IFT mutant embryos and embryos defective for the ciliary protein hennin/Arl13b, and suggest reduced levels of both Gli2/Gli3 activator and Gli3 repressor functions. We conclude that complex A and complex B factors play similar but distinct roles in ciliogenesis and Shh/Gli3 signaling.

Mouse Kif7/Costal2 is a cilia-associated protein that regulates Sonic hedgehog signaling

“…The expansion of ventral neural cell types in Kif7 maki mutants is much less pronounced than that seen in mutants that lack Patched1 or Sufu, core regulators of the pathway, or that lack IFT complex A proteins (8,9,25,35,36). The moderate activation of the Shh pathway could indicate that Kif7 has a relatively minor role in keeping the pathway off in the absence of ligand.…”

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Functions of primary cilium is regulated by large protein complexes involved in intraflagellar transport (IFT), which functions in retrograde and anterograde movement of cargo within the primary cilia (Scholey and Anderson, 2006). A number of mutations encoding IFT proteins involved in predominantly primary cilium anterograde IFT have been described, resulting in mice with Hh loss of function phenotypes (Huangfu et al, 2003;Cortellino et al, 2009). Several Hh components, including SMO and Gli molecules, are also present at the primary cilium upon Hh stimulation Rohatgi et al, 2009;Wang et al, 2009;Wilson et al, 2009a).…”

“…An SMO mutant lacking ciliary translocation blocks Hh signaling (Corbit et al, 2005). Gli3 processing is significantly affected by IFT mutants (Huangfu and Anderson, 2005;May et al, 2005;Cortellino et al, 2009), suggesting that SMO activates downstream molecules at the cilium. Current data indicate that localization of SMO to cilium is not sufficient to activate hedgehog signaling (Rohatgi et al, 2009;Wilson et al, 2009a).…”

Dual Phosphorylation of Suppressor of Fused (Sufu) by PKA and GSK3β Regulates Its Stability and Localization in the Primary Cilium

“…Two types of IFT complexes, IFT-A and IFT-B, carry out coordinated but distinct ciliary functions. Mutations in IFT88 and IFT172 of the IFT-B complex and the motor proteins Kif3a and Dync2h1 all prevent cilium assembly and attenuate Shh signaling (17,22), but mutation in IFT122 of the IFT-A complex results in altered cilium structure and elevates Shh signaling (23). A paradigm of Shh signaling through the primary cilium has emerged from a large body of experimental data (24,25).…”