THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia

Tran, Pamela V.; Haycraft, Courtney J.; Besschetnova, Tatiana Y.; Turbé-Doan, Annick; Stottmann, Rolf W.; Herron, Bruce J.; Chesebro, Allyson L.; Qiu, Haiyan; Scherz, Paul; Shah, Jagesh V.; Yoder, Bradley K.; Beier, David R.

doi:10.1038/ng.105

Cited by 311 publications

(454 citation statements)

References 46 publications

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“…However, MCHR1 was often associated with bulges along the cilium in Bbs3 −/− cells. These bulges are similar to those found in the tracheal and ependymal cilia of BBS mutant mice (18,23), and reminiscent of bulges found in IFT complex A mutants (36,37). Similarly, endogenous Smo accumulates inside cilia without ligand stimulation.…”

Section: Discussionsupporting

confidence: 75%

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

Zhang

Nishimura

Seo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

133

164

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Bardet-Biedl syndrome (BBS) is a heterogeneous disorder characterized by obesity, retinopathy, polydactyly, and congenital anomalies. The incidence of hypertension and diabetes are also increased in BBS patients. Mutation of 16 genes independently causes BBS, and seven BBS proteins form the BBSome that promotes ciliary membrane elongation. BBS3 (ARL6), an ADP ribosylation factor-like small GTPase, is not part of the BBSome complex. The in vivo function of BBS3 is largely unknown. Here we developed a Bbs3 knockout model and demonstrate that Bbs3 −/− mice develop BBS-associated phenotypes, including retinal degeneration, male infertility, and increased body fat. Interestingly, Bbs3 −/− mice develop some unique phenotypes not seen in other BBS knockout models: no overt obesity, severe hydrocephalus, and elevated blood pressure (shared by some but not all BBS gene knockout mice). We found that endogenous BBS3 and the BBSome physically interact and depend on each other for their ciliary localization. This finding explains the phenotypic similarity between Bbs3 −/− mice and BBSome subunit knockout mice. Loss of Bbs3 does not affect BBSome formation but disrupts normal localization of melanin concentrating hormone receptor 1 to ciliary membranes and affects retrograde transport of Smoothened inside cilia. We also show that the endogenous BBSome and BBS3 associate with membranes and the membrane association of the BBSome and BBS3 are not interdependent. Differences between BBS mouse models suggest nonoverlapping functions to individual BBS protein.

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Section: Discussionsupporting

confidence: 75%

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

Zhang

Nishimura

Seo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

133

164

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“…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.…”

Section: Kif7 Acts As Both a Negative And Positive Regulator Of Shh Smentioning

confidence: 97%

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

Liem

He²,

Ocbina³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

256

279

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Mammalian Sonic hedgehog (Shh) signaling is essential for embryonic development and stem cell maintenance and has critical roles in tumorigenesis. Although core components of the Shh pathway are conserved in evolution, important aspects of mammalian Shh signaling are not shared with the Drosophila pathway. Perhaps the most dramatic difference between the Drosophila and mammalian pathways is that Shh signaling in the mouse requires a microtubule-based organelle, the primary cilium. Proteins that are required for the response to Shh are enriched in the cilium, but it is not clear why the cilium provides an appropriate venue for signal transduction. Here, we demonstrate that Kif7, a mammalian homologue of Drosophila Costal2 (Cos2), is a cilia-associated protein that regulates signaling from the membrane protein Smoothened (Smo) to Gli transcription factors. By using a Kif7 mutant allele identified in a reporter-based genetic screen, we show that, similar to Drosophila and zebrafish Cos2, mouse Kif7 acts downstream of Smo and upstream of Gli2 and has both negative and positive roles in Shh signal transduction. Mouse Kif7 activity depends on the presence of cilia and Kif7-eGFP localizes to base of the primary cilium in the absence of Shh. Activation of the Shh pathway promotes trafficking of Kif7-eGFP from the base to the tip of the cilium, and localization to the tip of the cilium is disrupted in a motor domain mutant. We conclude that Kif7 is a core regulator of Shh signaling that may also act as a ciliary motor.Gli2 ͉ intraflagellar transport ͉ smoothened ͉ neural tube ͉ ENU

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“…The A1 peptide tag is specifically recognized by the AcpS enzyme. Enzymatic activity transfers a Ppant group in the CoA substrate to a serine residue in the A1 tag ( (10,(19)(20)(21)(22)(23)(24). Cilial accumulation of A1::Smo::GFP in response to ShhN treatment was confirmed by costaining with two additional primary cilium markers-anti-Arl13b ( Fig.…”

mentioning

confidence: 92%

“…17). Multiple components of the Hh pathway localize to the primary cilium or its basal body, including Sonic Hedgehog (Shh) (10,18), Ptch1 (10), Smo (10,(19)(20)(21)(22)(23)(24), suppressor of Fused (suFU) (a key negative regulator of Gli activity), and Gli transcription factors (21,24,25). In the absence of Shh, Ptch1 is enriched in the primary cilium of cultured mammalian cells; its cilial localization is lost after engagement with Shh ligand (10).…”

mentioning

confidence: 99%

“…Interestingly, a tryptophan to leucine mutation in the 7th transmembrane helix bundle of Smo generates a dominant-active form (SmoA1), that constitutively localizes to the primary cilium (19,20). Downstream of Smo, suFU and Gli proteins concentrate in or about the primary cilium (21,24,25). Further, their normal function depends on the intact primary cilium (23,(25)(26)(27)(28).…”

mentioning

confidence: 99%

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Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation

Wang

Zhou

Walsh

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

179

170

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THM1 negatively modulates mouse sonic hedgehog signal transduction and affects retrograde intraflagellar transport in cilia

Cited by 311 publications

References 46 publications

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

Bardet-Biedl syndrome 3 (Bbs3) knockout mouse model reveals common BBS-associated phenotypes and Bbs3 unique phenotypes

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

Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation

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