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Tamara Caspary - One of the best experts on this subject based on the ideXlab platform.
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ARF Family GTPases with Links to Cilia.
American journal of physiology. Cell physiology, 2020Co-Authors: Skylar Fisher, Richard A Kahn, Tamara Caspary, Damian Kuna, Elizabeth SztulAbstract:The ARF superfamily of regulatory GTPases, including both the ARF and ARL proteins, control a multitude of cellular functions including aspects of vesicular traffic, lipid metabolism, mitochondrial architecture, the assembly and dynamics of the microtubule and actin cytoskeletons, and other pathways in cell biology. Considering their general utility, it is perhaps not surprising that increasingly ARF/ARLs have been found in connection to primary cilia. Here, we critically evaluate the current knowledge of the role four ARF/ARLs (ARF4, ARL3, ARL13B and ARL6) play in cilia and highlight key missing information that would help move our understanding forward. Importantly, these GTPases are themselves regulated by guanine nucleotide exchange factors (GEFs) that activate them and by GTPase activating proteins (GAPs) that act as both effectors and terminators of signaling. We believe that the identification of the GEFs and GAPs and better models of the actions of these GTPases and their regulators will provide a much deeper understanding and appreciation of the mechanisms that underly ciliary functions and the causes of a number of human ciliopathies.
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ARL13B regulates sonic hedgehog signaling from outside primary cilia
eLife, 2020Co-Authors: Eduardo D Gigante, Richard A Kahn, Anna A. Ivanova, Megan R Taylor, Tamara CasparyAbstract:: ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of ARL13B disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13BV358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed ARL13BV358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, ARL13BV358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. These data indicate that ARL13B's role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.
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the ciliary protein ARL13B functions outside of the primary cilium in shh mediated axon guidance
Cell Reports, 2019Co-Authors: Julien Ferent, Karel F Liem, Tamara Caspary, Laura E Mariani, Sandii Constable, Eduardo D Gigante, Emilie Legue, Frederic CharronAbstract:Summary The small GTPase ARL13B is enriched in primary cilia and regulates Sonic hedgehog (Shh) signaling. During neural development, Shh controls patterning and proliferation through a canonical, transcription-dependent pathway that requires the primary cilium. Additionally, Shh controls axon guidance through a non-canonical, transcription-independent pathway whose connection to the primary cilium is unknown. Here we show that inactivation of ARL13B results in defective commissural axon guidance in vivo. In vitro, we demonstrate that ARL13B functions autonomously in neurons for their Shh-dependent guidance response. We detect ARL13B protein in axons and growth cones, far from its well-established ciliary enrichment. To test whether ARL13B plays a non-ciliary function, we used an engineered, cilia-localization-deficient ARL13B variant and found that it was sufficient to mediate Shh axon guidance in vitro and in vivo. Together, these results indicate that, in addition to its ciliary role in canonical Shh signaling, ARL13B plays a cilia-independent role in Shh-mediated axon guidance.
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ARL13B regulates sonic hedgehog signaling from outside primary cilia
bioRxiv, 2019Co-Authors: Eduardo D Gigante, Richard A Kahn, Anna A. Ivanova, Megan R Taylor, Tamara CasparyAbstract:Abstract ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of ARL13B disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13BV358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed ARL13BV358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, ARL13BV358A/V358A cells displayed short cilia and lacked ciliary ARL3 and Inpp5e. These data indicate that ARL13B’s role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.
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disruption of the ciliary gtpase ARL13B suppresses sonic hedgehog overactivation and inhibits medulloblastoma formation
Proceedings of the National Academy of Sciences of the United States of America, 2018Co-Authors: Alyssa B Long, Tamara CasparyAbstract:Medulloblastoma (MB) is the most common malignant pediatric brain tumor, and overactivation of the Sonic Hedgehog (Shh) signaling pathway, which requires the primary cilium, causes 30% of MBs. Current treatments have known negative side effects or resistance mechanisms, so new treatments are necessary. Shh signaling mutations, like those that remove Patched1 (Ptch1) or activate Smoothened (Smo), cause tumors dependent on the presence of cilia. Genetic ablation of cilia prevents these tumors by removing Gli activator, but cilia are a poor therapeutic target since they support many biological processes. A more appropriate strategy would be to identify a protein that functionally disentangles Gli activation and ciliogenesis. Our mechanistic understanding of the ciliary GTPase ARL13B predicts that it could be such a target. ARL13B mutants retain short cilia, and loss of ARL13B results in ligand-independent, constitutive, low-level pathway activation but prevents maximal signaling without disrupting Gli repressor. Here, we show that deletion of ARL13B reduced Shh signaling levels in the presence of oncogenic SmoA1, suggesting ARL13B acts downstream of known tumor resistance mechanisms. Knockdown of ARL13B in human MB cell lines and in primary mouse MB cell culture decreased proliferation. Importantly, loss of ARL13B in a Ptch1-deleted mouse model of MB inhibited tumor formation. Postnatal depletion of ARL13B does not lead to any overt phenotypes in the epidermis, liver, or cerebellum. Thus, our in vivo and in vitro studies demonstrate that disruption of ARL13B inhibits cilia-dependent oncogenic Shh overactivation.
Jinghua Hu - One of the best experts on this subject based on the ideXlab platform.
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axoneme polyglutamylation regulated by joubert syndrome protein ARL13B controls ciliary targeting of signaling molecules
Nature Communications, 2018Co-Authors: Kai He, Tao Xu, Yan Li, Allen Hodge, Qing Zhang, Julia Torline, Yan Huang, Jian Zhao, Kun Ling, Jinghua HuAbstract:Tubulin polyglutamylation is a predominant axonemal post-translational modification. However, if and how axoneme polyglutamylation is essential for primary cilia and contribute to ciliopathies are unknown. Here, we report that Joubert syndrome protein ARL13B controls axoneme polyglutamylation, which is marginally required for cilia stability but essential for cilia signaling. ARL13B interacts with RAB11 effector FIP5 to promote cilia import of glutamylase TTLL5 and TTLL6. Hypoglutamylation caused by a deficient ARL13B-RAB11-FIP5 trafficking pathway shows no effect on ciliogenesis, but promotes cilia disassembly and, importantly, impairs cilia signaling by disrupting the proper anchoring of sensory receptors and trafficking of signaling molecules. Remarkably, depletion of deglutamylase CCP5, the predominant cilia deglutamylase, effectively restores hypoglutamylation-induced cilia defects. Our study reveals a paradigm that tubulin polyglutamylation is a major contributor for cilia signaling and suggests a potential therapeutic strategy by targeting polyglutamylation machinery to promote ciliary targeting of signaling machineries and correct signaling defects in ciliopathies.
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Molecular views of Arf-like small GTPases in cilia and ciliopathies
Experimental Cell Research, 2013Co-Authors: Qing Zhang, Jinghua Hu, Kun LingAbstract:Abstract The primary cilia are microtubule-based organelles that protrude from most of the eukaryotic cells. Recognized as the cell's antenna, primary cilium functions as a signaling hub for many physiologically and developmentally important signaling cascades. Ciliary dysfunction causes a wide spectrum of syndromic human genetic diseases collectively termed “ciliopathies”. Mounting evidences have shown that various small GTPases have been implicated in the context of cilia as well as human ciliopathies. However, how these small GTPases affect cilia formation and function remains poorly understood. Here we review and discuss the ciliary role of three Arf-like small GTPases (Arls), Arl3, Arl6, and ARL13B.
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SUMOylation of the small GTPase ARL-13 promotes ciliary targeting of sensory receptors.
Journal of Cell Biology, 2013Co-Authors: Yujie Li, Qing Zhang, Kun Ling, Yuxia Zhang, Jinghua HuAbstract:Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13–null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.
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SUMOylation of the small GTPase ARL-13 promotes ciliary targeting of sensory receptorsARL-13 and SUMOylation
Journal of Cell Biology, 2012Co-Authors: Yujie Li, Qing Zhang, Kun Ling, Yuxia Zhang, Jinghua HuAbstract:Primary cilia serve as cellular antenna for various sensory signaling pathways. However, how the sensory receptors are properly targeted to the ciliary surface remains poorly understood. Here, we show that UBC-9, the sole E2 small ubiquitin-like modifier (SUMO)-conjugating enzyme, physically interacts with and SUMOylates the C terminus of small GTPase ARL-13, the worm orthologue of ARL13B that mutated in ciliopathy Joubert syndrome. Mutations that totally abolish the SUMOylation of ARL-13 do not affect its established role in ciliogenesis, but fail to regulate the proper ciliary targeting of various sensory receptors and consequently compromise the corresponding sensory functions. Conversely, constitutively SUMOylated ARL-13 fully rescues all ciliary defects of arl-13-null animals. Furthermore, SUMOylation modification of human ARL13B is required for the ciliary entry of polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease. Our data reveal a novel but conserved role for the SUMOylation modification of ciliary small GTPase ARL13B in specifically regulating the proper ciliary targeting of various sensory receptors.
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The small GTPases ARL-13 and ARL-3 coordinate intraflagellar transport and ciliogenesis
Journal of Cell Biology, 2010Co-Authors: Yujie Li, Kun Ling, Yuxia Zhang, Jinghua HuAbstract:Intraflagellar transport (IFT) machinery mediates the bidirectional movement of cargos that are required for the assembly and maintenance of cilia. However, little is known about how IFT is regulated in vivo. In this study, we show that the small guanosine triphosphatase (GTPase) adenosine diphosphate ribosylation factor–like protein 13 (ARL-13) encoded by the Caenorhabditis elegans homologue of the human Joubert syndrome causal gene ARL13B, localizes exclusively to the doublet segment of the cilium. arl-13 mutants have shortened cilia with various ultrastructural deformities and a disrupted association between IFT subcomplexes A and B. Intriguingly, depletion of ARL-3, another ciliary small GTPase, partially suppresses ciliogenesis defects in arl-13 mutants by indirectly restoring binding between IFT subcomplexes A and B. Rescue of arl-13 mutants by ARL-3 depletion is mediated by an HDAC6 deacetylase-dependent pathway. Thus, we propose that two conserved small GTPases, ARL-13 and ARL-3, coordinate to regulate IFT and that perturbing this balance results in cilia deformation.
Cynthia Y He - One of the best experts on this subject based on the ideXlab platform.
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flagellar targeting of an arginine kinase requires a conserved lipidated protein intraflagellar transport lift pathway in trypanosoma brucei
Journal of Biological Chemistry, 2020Co-Authors: Maneesha Pandey, Yameng Huang, Cynthia Y HeAbstract:Both intraflagellar transport (IFT) and lipidated protein intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility, and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases ARL13B and Arl3 in the cilium. Our previous studies have revealed a single ARL13B ortholog in the evolutionarily divergent Trypanosoma brucei, the causative agent of African sleeping sickness. TbArl13 catalyzes two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 has been identified in T. brucei genome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting to and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacted with TbUnc119 in a GTP-dependent manner, suggesting functional specialization of Arl3-GTPases in T. brucei These results establish the function of TbUnc119 as a myristoylated cargo carrier and support the presence of a conserved LIFT pathway in T. brucei.
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Flagellar targeting of an arginine kinase requires the conserved Lipidated Intraflagellar Transport (LIFT) pathway in Trypanosoma brucei
bioRxiv, 2020Co-Authors: Maneesha Pandey, Yameng Huang, Cynthia Y HeAbstract:Both intraflagellar transport (IFT) and lipidated intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases ARL13B and Arl3 in the cilium. Our previous studies revealed a single ARL13B ortholog in the evolutionarily divergent Trypanosoma brucei. TbArl13 catalyses two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 was identified in T. brucei genome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacts with TbUnc119 in a GTP-dependant manner, suggesting functional specialization of Arl3-GTPases in T. brucei. This study establishes the function of TbUnc119 as a myristoylated cargo carrier and supports the presence of a conserved LIFT pathway in T. brucei.
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the unusual flagellar targeting mechanism and functions of the trypanosome ortholog of the ciliary gtpase ARL13B
Journal of Cell Science, 2018Co-Authors: Yiliu Zhang, Yameng Huang, Amrita Srivathsan, Cynthia Y HeAbstract:The small GTPase ARL13B is one of the most conserved and ancient ciliary proteins. In human and animals, ARL13B is primarily associated with the ciliary membrane, where it acts as a Guanine-nucleotide Exchange Factor (GEF) for Arl3 and is implicated in a variety of ciliary and cellular functions. We have identified and characterized TbArl13, the sole ARL13B homologue in the evolutionarily divergent, protozoan parasite Trypanosoma brucei. TbArl13 has conserved flagellar functions and exhibits catalytic activity towards two different TbArl3 homologues. However, TbArl13 is distinctly associated with the axoneme through a dimerization/docking (D/D) domain. Replacing the D/D domain with a flagellar membrane protein created a viable alternative to the wild-type TbArl13 in our RNA interference (RNAi)-based rescue assay. Therefore, flagellar enrichment is crucial for TbArl13 but mechanisms to achieve this could be flexible. Our findings thus extended the understanding of ARL13B and ARL13B-Arl3 pathway in a divergent flagellate of medical importance.
Duarte C Barral - One of the best experts on this subject based on the ideXlab platform.
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ARL13B interferes with α tubulin acetylation
Cilia, 2015Co-Authors: Petra Pintado, Cecilia Seixas, Duarte C Barral, Susana S LopesAbstract:Methods We used the zebrafish Kupffer’s vesicle as a dynamic ciliary growth system and performed a seven hour timecourse experiment comparing the length of cilia measured by ARL13B-GFP or by acetylated a-tubulin. In order to evaluate the specificity of the alterations in a-tubulin acetylation pattern, we overexpressed different ciliary proteins that were also reported to increase cilia length.
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ARL13B and the non muscle myosin heavy chain iia are required for circular dorsal ruffle formation and cell migration
Journal of Cell Science, 2014Co-Authors: Cristina Casalou, Cecilia Seixas, Jose S Ramalho, Ana Portelinha, Petra Pintado, Mafalda Barros, Susana S Lopes, Duarte C BarralAbstract:ABSTRACT The Arf-like protein ARL13B has been implicated in ciliogenesis and Sonic hedgehog signaling. Furthermore, we have previously shown that it regulates endocytic recycling traffic and interacts with actin. Herein, we report that the non-muscle myosin heavy chain IIA, also known as Myh9, is an ARL13B effector. Moreover, we found that both proteins localized to circular dorsal ruffles (CDRs) induced by platelet-derived growth factor stimulation and are required for their formation. CDRs are ring-shaped actin-dependent structures formed on the dorsal cell surface and are involved in diverse processes, such as macropinocytosis, integrin recycling, internalization of receptor tyrosine kinases and cell migration. We found that ARL13B or Myh9 silencing impaired cell migration, suggesting that ARL13B is required for this function through the interaction with Myh9. Moreover, ARL13B silencing impaired neural crest cell migration in zebrafish embryos. Furthermore, we showed that ARL13B is required for the formation of CDRs in migrating cells. Thus, our results indicate a new role for ARL13B in actin cytoskeleton remodeling through the interaction with Myh9, by driving the formation of CDRs necessary for cell migration.
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ARL13B influences cilia length in the zebrafish kupffer s vesicle
Cilia, 2013Co-Authors: Petra Pintado, Duarte C Barral, Susana S LopesAbstract:Joubert Syndrome is a ciliopathy that can be caused by a mutation in ARL13B protein. This syndrome is characterized by problems in embryonic development, especially at the neurological level. ARL13B is a protein that belongs to the small GTPase family, but presents the double size of a normal GTPase, because it has a different C-terminus with a coiled-coil domain and proline rich region. It is known that ARL13B localizes to the cilium and recent data showed that ARL13B is in the ciliary membrane. However the molecular function of ARL13B is unknown. This work is based on a functional study of this protein where we used zebrafish as a vertebrate model organism to study the embryonic development in a situation of loss or gain of function of ARL13B. In both situations we observed cardiac edema and abnormal body curvature. This work shows that in an over-expression situation cilia length is increased in the Kupffer’s vesicle, leading to randomization of the left-right gene expression cascade. This study contributes to a better understanding of ARL13B protein function in an organism since its molecular mechanism is not yet known, and provides new information on the localization of this protein in motile cilia. Publisher's note Due to an administrative error this abstract was omitted from the original supplement submission and thus the publication was updated on 26 April 2013.
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ARL13B influences cilia length in the zebrafish Kupffer’s vesicle
Cilia, 2013Co-Authors: Petra Pintado, Duarte C Barral, Susana LopesAbstract:Joubert Syndrome is a ciliopathy that can be caused by a mutation in ARL13B protein. This syndrome is characterized by problems in embryonic development, especially at the neurological level. ARL13B is a protein that belongs to the small GTPase family, but presents the double size of a normal GTPase, because it has a different C-terminus with a coiled-coil domain and proline rich region. It is known that ARL13B localizes to the cilium and recent data showed that ARL13B is in the ciliary membrane. However the molecular function of ARL13B is unknown. This work is based on a functional study of this protein where we used zebrafish as a vertebrate model organism to study the embryonic development in a situation of loss or gain of function of ARL13B. In both situations we observed cardiac edema and abnormal body curvature. This work shows that in an over-expression situation cilia length is increased in the Kupffer’s vesicle, leading to randomization of the left-right gene expression cascade. This study contributes to a better understanding of ARL13B protein function in an organism since its molecular mechanism is not yet known, and provides new information on the localization of this protein in motile cilia. Publisher's note Due to an administrative error this abstract was omitted from the original supplement submission and thus the publication was updated on 26 April 2013.
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ARL13B regulates endocytic recycling traffic
Proceedings of the National Academy of Sciences of the United States of America, 2012Co-Authors: Duarte C Barral, Salil Garg, Cristina Casalou, Gerald F Watts, Jose Luis Sandoval, Jose S Ramalho, Michael B BrennerAbstract:Intracellular recycling pathways play critical roles in internalizing membrane and fluid phase cargo and in balancing the inflow and outflow of membrane and cell surface molecules. To identify proteins involved in the regulation of endocytic recycling, we used an shRNA trafficking library and screened for changes in the surface expression of CD1a antigen-presenting molecules that follow an endocytic recycling route. We found that silencing of the ADP-ribosylation factor (Arf)-like small GTPase ARL13B led to a decrease in CD1a surface expression, diminished CD1a function, and delayed CD1a recycling, suggesting that ARL13B is involved in the regulation of endocytic recycling traffic. ARL13B appears to be required for the major route of endocytic trafficking, causing clustering of early endosomes and leading to the accumulation of endocytic cargo. Moreover, ARL13B colocalized with markers of the endocytic recycling pathway followed by CD1a, namely Arf6 and Rab22a. We also detected an interaction between ARL13B and the actin cytoskeleton. ARL13B was previously implicated in cilia formation and function. Our present results indicate a previously unidentified role for ARL13B in endocytic recycling traffic and suggest a link between ARL13B function and the actin cytoskeleton.
Susana S Lopes - One of the best experts on this subject based on the ideXlab platform.
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ARL13B interferes with α tubulin acetylation
Cilia, 2015Co-Authors: Petra Pintado, Cecilia Seixas, Duarte C Barral, Susana S LopesAbstract:Methods We used the zebrafish Kupffer’s vesicle as a dynamic ciliary growth system and performed a seven hour timecourse experiment comparing the length of cilia measured by ARL13B-GFP or by acetylated a-tubulin. In order to evaluate the specificity of the alterations in a-tubulin acetylation pattern, we overexpressed different ciliary proteins that were also reported to increase cilia length.
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ARL13B and the non muscle myosin heavy chain iia are required for circular dorsal ruffle formation and cell migration
Journal of Cell Science, 2014Co-Authors: Cristina Casalou, Cecilia Seixas, Jose S Ramalho, Ana Portelinha, Petra Pintado, Mafalda Barros, Susana S Lopes, Duarte C BarralAbstract:ABSTRACT The Arf-like protein ARL13B has been implicated in ciliogenesis and Sonic hedgehog signaling. Furthermore, we have previously shown that it regulates endocytic recycling traffic and interacts with actin. Herein, we report that the non-muscle myosin heavy chain IIA, also known as Myh9, is an ARL13B effector. Moreover, we found that both proteins localized to circular dorsal ruffles (CDRs) induced by platelet-derived growth factor stimulation and are required for their formation. CDRs are ring-shaped actin-dependent structures formed on the dorsal cell surface and are involved in diverse processes, such as macropinocytosis, integrin recycling, internalization of receptor tyrosine kinases and cell migration. We found that ARL13B or Myh9 silencing impaired cell migration, suggesting that ARL13B is required for this function through the interaction with Myh9. Moreover, ARL13B silencing impaired neural crest cell migration in zebrafish embryos. Furthermore, we showed that ARL13B is required for the formation of CDRs in migrating cells. Thus, our results indicate a new role for ARL13B in actin cytoskeleton remodeling through the interaction with Myh9, by driving the formation of CDRs necessary for cell migration.
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ARL13B influences cilia length in the zebrafish kupffer s vesicle
Cilia, 2013Co-Authors: Petra Pintado, Duarte C Barral, Susana S LopesAbstract:Joubert Syndrome is a ciliopathy that can be caused by a mutation in ARL13B protein. This syndrome is characterized by problems in embryonic development, especially at the neurological level. ARL13B is a protein that belongs to the small GTPase family, but presents the double size of a normal GTPase, because it has a different C-terminus with a coiled-coil domain and proline rich region. It is known that ARL13B localizes to the cilium and recent data showed that ARL13B is in the ciliary membrane. However the molecular function of ARL13B is unknown. This work is based on a functional study of this protein where we used zebrafish as a vertebrate model organism to study the embryonic development in a situation of loss or gain of function of ARL13B. In both situations we observed cardiac edema and abnormal body curvature. This work shows that in an over-expression situation cilia length is increased in the Kupffer’s vesicle, leading to randomization of the left-right gene expression cascade. This study contributes to a better understanding of ARL13B protein function in an organism since its molecular mechanism is not yet known, and provides new information on the localization of this protein in motile cilia. Publisher's note Due to an administrative error this abstract was omitted from the original supplement submission and thus the publication was updated on 26 April 2013.
