Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling

Norman, Ryan X.; Ko, Hyuk Wan; Huang, Viola; Eun, Christine M.; Abler, Lisa L.; Zhang, Zhen; Sun, Xin; Eggenschwiler, Jonathan

doi:10.1093/hmg/ddp113

Cited by 94 publications

(115 citation statements)

References 119 publications

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“…3A; Supplemental Fig. S2D; Norman et al 2009). Tubby family proteins have been observed to relocalize to the nucleus when displaced from the membrane (Santagata et al 2001).…”

Section: Tulp3 Localizes To the Primary Cilia But Does Not Affect CImentioning

confidence: 99%

“…It is surprising, however, that mammalian neural tube phenotypes of mutants of IFT-A subunits differ from those of the IFT motor dynein 2 (Tran et al 2008;Cortellino et al 2009;Goetz and Anderson 2010), while Tulp3 alleles also show overactivation of the Hh pathway similar to the IFT-A mutants (Norman et al 2009;Patterson et al 2009). IFT-A associates with TULP3, and has both an early role in delivering TULP3 to cilia and another role in retrograde traffic of TULP3, compromising TULP3 function in either case.…”

Section: Tulp3 Is An Effector Of the Ift-a Complex Genes And Developmenmentioning

confidence: 99%

“…In the absence of Hh, inactive Smo is transported laterally from the adjacent plasma membrane to the ciliary membrane at a baseline level, and knockdown of Dync2h1 causes Smo to accumulate in the untreated cilia (Ocbina and Anderson 2008;Milenkovic et al 2009). However, Tulp3 and the IFT-A complex knockdowns do not cause accumulation of Smo in untreated cells, and genetic epistasis experiments suggest that Tulp3 function is independent of Smo (Norman et al 2009;Patterson et al 2009). In addition, unlike Dync2h1 knockdowns, Tulp3 and IFT-A complex knockdowns do not affect Gli3 processing or ciliary translocation (see also Norman et al 2009;Patterson et al 2009).…”

Section: Tulp3 Is An Effector Of the Ift-a Complex Genes And Developmenmentioning

confidence: 99%

“…However, Tulp3 and the IFT-A complex knockdowns do not cause accumulation of Smo in untreated cells, and genetic epistasis experiments suggest that Tulp3 function is independent of Smo (Norman et al 2009;Patterson et al 2009). In addition, unlike Dync2h1 knockdowns, Tulp3 and IFT-A complex knockdowns do not affect Gli3 processing or ciliary translocation (see also Norman et al 2009;Patterson et al 2009). These experiments suggest that Tulp3 and the IFT-A complex have functions distinct from Dync2h1 in the Hh signaling pathway.…”

Section: Tulp3 Is An Effector Of the Ift-a Complex Genes And Developmenmentioning

confidence: 99%

“…Tulp3 has been described recently as a negative regulator of Hh signaling in the mouse embryo (Cameron et al 2009;Norman et al 2009;Patterson et al 2009). Genetic epistasis experiments suggest that, similar to the IFT-A subunit Thm1, Tulp3 restricts Gli2 activity in an IFT-dependent manner downstream from Sonic hedgehog (Norman et al 2009;Patterson et al 2009). Although Tulp3 and Thm1 act as negative regulators of the Hh pathway, their roles remain unclear.…”

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confidence: 99%

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TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia

Mukhopadhyay¹,

Wen²,

Chih³

et al. 2010

Genes Dev.

362

540

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Primary cilia function as a sensory signaling compartment in processes ranging from mammalian Hedgehog signaling to neuronal control of obesity. Intraflagellar transport (IFT) is an ancient, conserved mechanism required to assemble cilia and for trafficking within cilia. The link between IFT, sensory signaling, and obesity is not clearly defined, but some novel monogenic obesity disorders may be linked to ciliary defects. The tubby mouse, which presents with adult-onset obesity, arises from mutation in the Tub gene. The tubby-like proteins comprise a related family of poorly understood proteins with roles in neural development and function. We find that specific Tubby family proteins, notably Tubby-like protein 3 (TULP3), bind to the IFT-A complex. IFT-A is linked to retrograde ciliary transport, but, surprisingly, we find that the IFT-A complex has a second role directing ciliary entry of TULP3. TULP3 and IFT-A, in turn, promote trafficking of a subset of G protein-coupled receptors (GPCRs), but not Smoothened, to cilia. Both IFT-A and membrane phosphoinositide-binding properties of TULP3 are required for ciliary GPCR localization. TULP3 and IFT-A proteins both negatively regulate Hedgehog signaling in the mouse embryo, and the TULP3–IFT-A interaction suggests how these proteins cooperate during neural tube patterning.

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“…3A; Supplemental Fig. S2D; Norman et al 2009). Tubby family proteins have been observed to relocalize to the nucleus when displaced from the membrane (Santagata et al 2001).…”

Section: Tulp3 Localizes To the Primary Cilia But Does Not Affect CImentioning

confidence: 99%

Section: Tulp3 Is An Effector Of the Ift-a Complex Genes And Developmenmentioning

confidence: 99%

Section: Tulp3 Is An Effector Of the Ift-a Complex Genes And Developmenmentioning

confidence: 99%

Section: Tulp3 Is An Effector Of the Ift-a Complex Genes And Developmenmentioning

confidence: 99%

mentioning

confidence: 99%

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TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia

Mukhopadhyay¹,

Wen²,

Chih³

et al. 2010

Genes Dev.

362

540

View full text Add to dashboard Cite

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The relationship between sonic Hedgehog signaling, cilia, and neural tube defects

Murdoch

Copp

2010

Birth Defects Research

172

185

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The Hedgehog signalling pathway is essential for many aspects of normal embryonic development, including formation and patterning of the neural tube. Absence of Shh ligand is associated with the midline defect holoprosencephaly, while increased Shh signalling is associated with exencephaly and spina bifida. To complicate this apparently simple relationship, mutation of proteins required for function of cilia often leads to impaired Shh signalling and to disruption of neural tube closure. In this manuscript, we review the literature on Shh pathway mutants and discuss the relationship between Shh signalling, cilia and neural tube defects.

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G‐protein‐coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning

Hwang

Mukhopadhyay²

2014

Birth Defects Research

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The primary cilium is critical in sonic hedgehog (Shh)-dependent ventral patterning of the vertebrate neural tube. Most mutants that cause disruption of the cilium result in decreased Shh signaling in the neural tube. In contrast, mutations in the intraflagellar complex A (IFT-A) and the tubby family protein, Tulp3, result in increased Shh signaling in the neural tube. Proteomic analysis of Tulp3-binding proteins first pointed to the role of the IFT-A complex in trafficking Tulp3 into the cilia. Tulp3 directs trafficking of rhodopsin family G-protein-coupled receptors (GPCRs) to the cilia, suggesting the role of a GPCR in mediating the paradoxical effects of the Tulp3/IFT-A complex in causing increased Shh signaling. Gpr161 has recently been identified as a Tulp3/IFT-A-regulated GPCR that localizes to the primary cilium. A null knock-out mouse model of Gpr161 phenocopies Tulp3 and IFT-A mutants, and causes increased Shh signaling throughout the neural tube. In the absence of Shh, the bifunctional Gli transcription factors are proteolytically processed into repressor forms in a protein kinase A (PKA) -dependent and cilium-dependent manner. Gpr161 activity results in increased cAMP levels in a Gαs -coupled manner, and determines processing of Gli3. Shh signaling also results in removal of Gpr161 from the cilia, suggesting that Gpr161 functions in a positive feedback loop in the Shh pathway. As PKA-null and Gαs mutant embryos also exhibit increased Shh signaling in the neural tube, Gpr161 is a strong candidate for a GPCR that regulates ciliary cAMP levels, and activates PKA in close proximity to the cilia.

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Tubby-like protein 3 (TULP3) regulates patterning in the mouse embryo through inhibition of Hedgehog signaling

Cited by 94 publications

References 119 publications

TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia

TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia

The relationship between sonic Hedgehog signaling, cilia, and neural tube defects

G‐protein‐coupled receptors and localized signaling in the primary cilium during ventral neural tube patterning

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