Gli2a protein localization reveals a role for Iguana/DZIP1 in primary ciliogenesis and a dependence of Hedgehog signal transduction on primary cilia in the zebrafish

Kim, Hyejeong Rosemary; Richardson, Jo; Eeden, Freek van; Ingham, Philip W.

doi:10.1186/1741-7007-8-65

Cited by 51 publications

(65 citation statements)

References 47 publications

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“…Cilia length is regulated by cAMP levels (31,32). However, the observation that stable expression of Smo and GRK2 can affect cilia length is consistent with a previous suggestion that the Hh pathway by itself may influence the length of primary cilia (33). Surprisingly, GRK2 does not have to traffic into the cilia or to the basal body in order to exert its effect.…”

Section: Discussionsupporting

confidence: 67%

Growth Arrest Specific 8 (Gas8) and G Protein-coupled Receptor Kinase 2 (GRK2) Cooperate in the Control of Smoothened Signaling

Evron

Philipp

Lü

et al. 2011

Journal of Biological Chemistry

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The G protein-coupled receptor (GPCR)-like molecule Smoothened (Smo) undergoes dynamic intracellular trafficking modulated by the microtubule associated kinase GRK2 and recruitment of ␤-arrestin. Of this trafficking, especially the translocation of Smo into primary cilia and back to the cytoplasm is essential for the activation of Hedgehog (Hh) signaling in vertebrates. The complete mechanism of this bidirectional transport, however, is not completely understood. Here we demonstrate that Growth Arrest Specific 8 (Gas8), a microtubule associated subunit of the Dynein Regulatory Complex (DRC), interacts with Smo to modulate this process. Gas8 knockdown in ciliated cells reduces Smo signaling activity and ciliary localization whereas overexpression stimulates Smo activity in a GRK2-dependent manner. The C terminus of Gas8 is important for both Gas8 interaction with Smo and facilitating Smo signaling. In zebrafish, knocking down Gas8 results in attenuated Hh transcriptional responses and impaired early muscle development. These effects can be reversed by the co-injection of Gas8 mRNA or by constitutive activation of the downstream Gli transcription factors. Furthermore, Gas8 and GRK2 display a synergistic effect on zebrafish early muscle development and some effects of GRK2 knockdown can be rescued by Gas8 mRNA. Interestingly, Gas8 does not interfere with cilia assembly, as the primary cilia architecture is unchanged upon Gas8 knock down or heterologous expression. This is in contrast to cells stably expressing both GRK2 and Smo, in which cilia are significantly elongated. These results identify Gas8 as a positive regulator of Hh signaling that cooperates with GRK2 to control Smo signaling. Smoothened (Smo)5 is a G protein-coupled receptor (GPCR)-like protein that serves as the main transducer of the Hedgehog (Hh) signaling pathway, regulating many aspects of embryonic development. Loss of function of components of this pathway leads to human developmental disorders, including holoprosencephaly, polydactyly, craniofacial, and skeletal malformation (1, 2), while inappropriate activation of the pathway is linked to a wide range of malignancies (3). Data from mammalian cell culture, mice, and zebrafish have implicated Smo trafficking into the primary cilia by intraflagellar transport (IFT) particles as an essential step in Hh downstream signaling (reviewed in Refs. 4, 5). Smo translocation results in the accumulation of transcriptionally active Gli (GliA) at the tip of the cilia, which is then transported out of the cilia to promote Hh target gene expression (4). Similar to classic GPCRs, phosphorylation of active Smo by the GPCR kinase 2 (GRK2) and recruitment of ␤-arrestin results in Smo internalization (6), and both GRK2 and ␤-arrestin play a positive role in Smo signaling as they do in selective forms of GPCR signaling (7,8). Interestingly, GRK2 has been reported as a microtubule associated kinase that directly phosphorylates tubulin following GPCR stimulation (9). GRK2 has also been shown to promote signaling thro...

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Section: Discussionsupporting

confidence: 67%

Growth Arrest Specific 8 (Gas8) and G Protein-coupled Receptor Kinase 2 (GRK2) Cooperate in the Control of Smoothened Signaling

Evron

Philipp

Lü

et al. 2011

Journal of Biological Chemistry

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“…(6). Recent studies have shown that zebrafish with either mutations in the Igu gene (the zebrafish Dzip1 homolog) or Igu morpholino knockdown lacks primary cilia (41)(42)(43). However, the underlying mechanism of the cilia defect is unknown.…”

Section: Discussionmentioning

confidence: 99%

Centrosomal Protein DZIP1 Regulates Hedgehog Signaling by Promoting Cytoplasmic Retention of Transcription Factor GLI3 and Affecting Ciliogenesis

Wang¹,

Low²,

Liu

et al. 2013

Journal of Biological Chemistry

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Background: All known cilia-related proteins regulate Hedgehog signaling through their role in ciliogenesis. Results: The centrosomal protein DZIP1 interacts with and sequesters GLI3 transcription factor in the cytoplasm and also regulates ciliogenesis. Conclusion: DZIP1 is the first known cilia-related protein that regulates Hedgehog signaling through a dual mechanism. Significance: Understanding how DZIP1 regulates Hedgehog signaling provides new insights into the molecular mechanism of Hedgehog signal transduction.

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“…Zebrafish embryos that lack functions of Ift88 or Talpid3 have no primary cilia and are deficient for high-level Hh signaling but have expanded low-level signaling (Ben et al, 2011;Huang and Schier, 2009), suggesting that in zebrafish, cilia promote efficient Hh signaling. To test whether or not primary cilia, independent of apical Par protein functions, are necessary for neural progenitor maintenance, we examined dzip1 mutant embryos, which lack primary cilia and have a Hh signaling profile similar to that of Ift88 and Talpid3-deficient embryos (Wolff et al, 2004;Sekimizu et al, 2004;Kim et al, 2010;Huang and Schier, 2009;Tay et al, 2010). At 3 and 5 dpf, dzip1 mutant animals had similar numbers of Sox2 + and PH3…”

Section: Apical Par Proteins Mediate the Effects Of Mir-219 On Hh Sigmentioning

confidence: 99%

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

et al. 2016

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The transition of dividing neuroepithelial progenitors to differentiated neurons and glia is essential for the formation of a functional nervous system. Sonic hedgehog (Shh) is a mitogen for spinal cord progenitors, but how cells become insensitive to the proliferative effects of Shh is not well understood. Because Shh reception occurs at primary cilia, which are positioned within the apical membrane of neuroepithelial progenitors, we hypothesized that loss of apical characteristics reduces the Shh signaling response, causing cell cycle exit and differentiation. We tested this hypothesis using genetic and pharmacological manipulation, gene expression analysis and time-lapse imaging of zebrafish embryos. Blocking the function of miR-219, a microRNA that downregulates apical Par polarity proteins and promotes progenitor differentiation, elevated Shh signaling. Inhibition of Shh signaling reversed the effects of miR-219 depletion and forced expression of Shh phenocopied miR-219 deficiency. Time-lapse imaging revealed that knockdown of miR-219 function accelerates the growth of primary cilia, revealing a possible mechanistic link between miR-219-mediated regulation of apical Par proteins and Shh signaling. Thus, miR-219 appears to decrease progenitor cell sensitivity to Shh signaling, thereby driving these cells towards differentiation.

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Gli2a protein localization reveals a role for Iguana/DZIP1 in primary ciliogenesis and a dependence of Hedgehog signal transduction on primary cilia in the zebrafish

Cited by 51 publications

References 47 publications

Growth Arrest Specific 8 (Gas8) and G Protein-coupled Receptor Kinase 2 (GRK2) Cooperate in the Control of Smoothened Signaling

Growth Arrest Specific 8 (Gas8) and G Protein-coupled Receptor Kinase 2 (GRK2) Cooperate in the Control of Smoothened Signaling

Centrosomal Protein DZIP1 Regulates Hedgehog Signaling by Promoting Cytoplasmic Retention of Transcription Factor GLI3 and Affecting Ciliogenesis

miR-219 regulates neural progenitors by dampening apical Par protein-dependent Hedgehog signaling

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