RPGRIP1L

14,000,000 Leading Edge Experts on the ideXlab platform

Scan Science and Technology

Contact Leading Edge Experts & Companies

Scan Science and Technology

Contact Leading Edge Experts & Companies

The Experts below are selected from a list of 22985286 Experts worldwide ranked by ideXlab platform

Alexia Mahuzier - One of the best experts on this subject based on the ideXlab platform.

  • etude de la fonction du gene RPGRIP1L dans les processus de differenciation et de polarite cellulaire chez le poisson zebre
    2013
    Co-Authors: Alexia Mahuzier
    Abstract:

    Le cil primaire, present a la surface de la majorite des cellules chez les vertebres, a un role primordial dans le developpement embryonnaire et dans la modulation de voies de signalisation, notamment Hedgehog et Wnt. Des defauts de cette structure sont associes a des maladies hereditaires, les ciliopathies. Le gene RPGRIP1L est implique dans deux ciliopathies, le syndrome de Joubert de type B et le syndrome de Meckel, caracterisees par une polydactylie, des kystes renaux et des malformations du systeme nerveux central. RPGRIP1L code pour une proteine localisee principalement a la zone de transition des cils, une region impliquee dans le controle du trafic des proteines vers et hors du compartiment ciliaire. Mon projet de these a porte sur les fonctions de RPGRIP1L dans les processus de differenciation et de polarite cellulaire dans le systeme nerveux du poisson-zebre. Mon premier travail, base sur la perte de fonction de RPGRIP1L par injection de morpholino dans des embryons de poissons zebre, a mis a jour une fonction de RPGRIP1L dans la mise en place de la polarite planaire via la stabilisation de dishevelled, une proteine cle de la voie Wnt/PCP. J’ai ensuite etudie les fonctions plus tardives du gene RPGRIP1L et de son paralogue rpgrip1 dans la retine, via l’analyse de lignees de poissons zebre hypomorphes. Cette etude a montre l’existence de multiples isoformes de RPGRIP1L et suggere de nouvelles fonctions extra-ciliaires pour RPGRIP1L dans la morphogenese des photorecepteurs. L’ensemble de ce travail devrait permettre de mieux comprendre l’origine developpementale des anomalies cerebrales et retiniennes observees dans les ciliopathies.

  • Functional analysis of the transition zone protein RPGRIP1L during zebrafish development
    Cilia, 2012
    Co-Authors: Christine Vesque, Alexia Mahuzier, Isabelle Anselme, M Leroux-berger, Sylvie Schneider-maunoury
    Abstract:

    We investigated the function of RPGRIP1L during zebrafish development. RPGRIP1L encodes a protein localised at the ciliary transition zone and interacts functionally with NPH and MKS for the formation and function of the ciliary gate. The human RPGRIP1L gene is a causal gene in Meckel and Joubert type B syndromes, characterised by polydactyly, kidney cysts and central nervous system malformations. Using morpholinos injection, we show that loss of RPGRIP1L function leads to several early phenotypes such as convergent-extension phenotype, randomisation of left-right asymmetry and hydrocephaly. We focussed our study on the Wnt-PCP defects and we demonstrated that in the zebrafish floorplate, RPGRIP1L is required for correct positioning of the basal body along the planar polarity axis. We confirmed RPGRIP1L function on basal body positioning in the mechanosensory hair cells of the cochlea of the murine mutant for RPGRIP1L. Our results strongly suggest that RPGRIP1L is essential for recruiting and stabilizing dishevelled, a major actor of the PCP pathway, at the basal body and/or cilium. Indeed, in two different cell types, in the zebrafish floor plate and in the murine cochlea, dishevelled proteins are enriched at the cilium and/or basal body, and this localization is severely perturbed upon RPGRIP1L depletion. Finally, we demonstrate that, in the zebrafish floor plate, the function of RPGRIP1L in basal body positioning is mediated by dishevelled. We propose that RPGRIP1L participates in a protein complex required for recruiting and stabilizing dishevelled at the cilium, a process essential for planar polarization of the basal body.

  • dishevelled stablisation at the cilium by RPGRIP1L is essential for planar cell polarity
    Cilia, 2012
    Co-Authors: Sylvie Schneidermaunoury, Sophie Saunier, Helori-mael Gaudé, Isabelle Anselme, Alexia Mahuzier, Flora Silbermann, Margot Lerouxberger, Mireille Montcouquiol, Christine Vesque
    Abstract:

    Cilia are involved in planar polarity in different systems but the mechanisms by which they influence the polarization process are unclear [1]. In order to clarify this issue, we investigated the function of the ciliary gene RPGRIP1L (Ftm/NPHP8/MKS5) in the mammalian cochlear sensory epithelium and in the zebrafish floor plate. We and others have previously shown that mutations in the human RPGRIP1L gene cause Meckel and Joubert type B syndromes [2]. The RPGRIP1L protein is localised at the ciliary transition zone and is required for transduction of the Hh/ Gli pathway [3]. Our recent work has shown that RPGRIP1L patterns the telencephalon via the regulation of Gli3 proteolytic cleavage [4]. Here we show that in both the mammalian cochlear sensory epithelium and the zebrafish floor plate, RPGRIP1L is required for correct positioning of the basal body along the planar polarity axis. Our results strongly suggest that RPGRIP1L is essential for stabilizing the adaptor protein dishevelled at the basal body and/or cilium. Finally, we demonstrate that, in the zebrafish floor plate, the function of RPGRIP1L in basal body positioning is mediated by dishevelled. We propose that RPGRIP1L participates in a protein complex required for stabilizing dishevelled at the cilium, and that this stabilization is essential for asymmetric localization of the basal body along the planar polarity axis.

  • dishevelled stabilization by the ciliopathy protein RPGRIP1L is essential for planar cell polarity
    Journal of Cell Biology, 2012
    Co-Authors: Helori-mael Gaudé, Isabelle Anselme, Alexia Mahuzier, Valentina Grampa, Flora Silbermann
    Abstract:

    Cilia are at the core of planar polarity cellular events in many systems. However, the molecular mechanisms by which they influence the polarization process are unclear. Here, we identify the function of the ciliopathy protein RPGRIP1L in planar polarity. In the mouse cochlea and in the zebrafish floor plate, RPGRIP1L was required for positioning the basal body along the planar polarity axis. RPGRIP1L was also essential for stabilizing dishevelled at the cilium base in the zebrafish floor plate and in mammalian renal cells. In rescue experiments, we showed that in the zebrafish floor plate the function of RPGRIP1L in planar polarity was mediated by dishevelled stabilization. In cultured cells, RPGRIP1L participated in a complex with inversin and nephrocystin-4, two ciliopathy proteins known to target dishevelled to the proteasome, and, in this complex, RPGRIP1L prevented dishevelled degradation. We thus uncover a ciliopathy protein complex that finely tunes dishevelled levels, thereby modulating planar cell polarity processes.

Keiko Miyadera - One of the best experts on this subject based on the ideXlab platform.

  • variabilities in retinal function and structure in a canine model of cone rod dystrophy associated with rpgrip1 support multigenic etiology
    Scientific Reports, 2017
    Co-Authors: Felipe Pompeo Marinho, Gustavo D Aguirre, Simone Iwabe, Kendra Mcdaid, Evelyn Santana, Keiko Miyadera
    Abstract:

    Defects in the cilia gene RPGRIP1 cause Leber congenital amaurosis and cone-rod dystrophy in humans. A form of canine cone-rod dystrophy (cord1) was originally associated with a homozygous insertion in RPGRIP1 (RPGRIP1 ins/ins) as the primary disease locus while a homozygous deletion in MAP9 (MAP9 del/del) was later identified as a modifier associated with the early onset form. However, we find further variability in cone electroretinograms (ERGs) ranging from normal to absent in an extended RPGRIP1 ins/ins canine colony, irrespective of the MAP9 genotype. Ophthalmoscopically, cone ERGabsent RPGRIP1 ins/ins eyes show discolouration of the tapetal fundus with varying onset and disease progression, while sd-OCT reveals atrophic changes. Despite marked changes in cone ERG and retinal morphology, photopic vision-guided behaviour is comparable between normal and cone ERGabsent RPGRIP1 ins/ins littermates. Cone morphology of the dogs lacking cone ERG are truncated with shortened outer and inner segments. Immunohistochemically, cone ERGabsent RPGRIP1 ins/ins retinas have extensive L/M-opsin mislocalization, lack CNGB3 labelling in the L/M-cones, and lack GC1 in all cones. Our results indicate that cord1 is a multigenic disease in which mutations in neither RPGRIP1 nor MAP9 alone lead to visual deficits, and additional gene(s) contribute to cone-specific functional and morphologic defects.

  • Multiple Mechanisms Contribute to Leakiness of a Frameshift Mutation in Canine Cone-Rod Dystrophy
    2016
    Co-Authors: Keiko Miyadera, Cathryn S Mellersh, Ian Brierley, David R. Sargan
    Abstract:

    Mutations in RPGRIP1 are associated with early onset retinal degenerations in humans and dogs. Dogs homozygous for a 44 bp insertion including a polyA29 tract potentially leading to premature truncation of the protein, show cone rod degeneration. This is rapid and blinding in a colony of dogs in which the mutation was characterised but in dogs with the same mutation in the pet population there is very variable disease severity and rate of progression. Objective: We hypothesized that this variability must be associated with leakiness of the RPGRIP1 mutation, allowing continued RPGRIP1 production. The study was designed to discover mechanisms that might allow such leakiness. Methods: We analysed alternate start sites and splicing of RPGRIP1 transcripts; variability of polyAn length in the insertion and slippage at polyAn during transcription/translation. Results and Significance: We observed a low rate of use of alternative start codons having potential to allow forms of transcript not including the insertion, with the possibility of encoding truncated functional RPGRIP1 protein isoforms. Complex alternative splicing was observed, but did not increase this potential. Variable polyAn length was confirmed in DNA from different RPGRIP12/2 dogs, yet polyAn variability did not correspond with the clinical phenotypes and no individual was found that carried a polyAn tract capable of encoding an in-frame variant. Remarkably though, in luciferase reporter gene assays, out-of-frame inserts still allowed downstream reporter gene expression at some 40 % of the efficiency of in

  • Canine genome assembly correction facilitates identification of a MAP9 deletion as a potential age of onset modifier for RPGRIP1-associated canine retinal degeneration
    Mammalian Genome, 2016
    Co-Authors: Oliver P Forman, M E G Boursnell, Keiko Miyadera, Rebekkah J. Hitti, David Sargan, Cathryn S Mellersh
    Abstract:

    Retinal degeneration (RD) in the Miniature Long Haired Dachshund (MLHD) is a cone-rod dystrophy resulting in eventual blindness in affected individuals. In a previous study, a 44-nucleotide insertion (ins44) in exon 2 of RPGRIP1 was associated with RD. However, results on an extended population of MLHD revealed a variable RD onset age for ins44 homozygous dogs. Further investigations using a genome-wide association study comparing early onset and late onset RD cases identified an age of onset modifying locus for RD, approximately 30 Mb upstream of RPGRIP1 on chr15. In this investigation, target enriched sequencing identified a MAP9 deletion spanning approximately 22 kb associated with early RD onset. Identification of the deletion required correction to the CanFam3.1 genome build as canine MAP9 is part of a historic tandem duplication, resulting in incomplete assembly of this genome region. The deletion breakpoints were identified in MAP9 intron 10 and in a downstream partial MAP9 pseudogene. The fusion of these two genes, which we have called MAP9 _ EORD (microtubule-associated protein, early onset retinal degeneration), is in frame and is expressed at the RNA level, with the 3′ region containing several predicted deleterious variants. We speculate that MAP9 associates with α-tubulin in the basal body of the cilium. RPGRIP1 is also known to locate to the cilium, where it is closely associated with RPGR. RPGRIP1 mutations also cause redistribution of α-tubulin away from the ciliary region in photoreceptors. Hence, a MAP9 partial deficit is a particularly attractive candidate to synergise with a partial RPGRIP1 deficit to cause a more serious disease.

  • genome wide association study in rpgrip1 dogs identifies a modifier locus that determines the onset of retinal degeneration
    Mammalian Genome, 2012
    Co-Authors: Cathryn S Mellersh, M E G Boursnell, Keiko Miyadera, Kumiko Kato, David R. Sargan
    Abstract:

    Cone-rod dystrophy (CRD) is a form of inherited retinal degeneration (RD) causing blindness in man as well as in several breeds of dog. Previously, a 44 bp insertion in RPGRIP1 (retinitis pigmentosa GTPase regulator interacting protein-1) was associated with a recessive early-onset CRD (cone-rod dystrophy 1, cord1) in a Miniature longhaired dachshund (MLHD) research colony. Yet in the MLHD pet population, extensive range of the onset age has been observed among RD cases, with some RPGRIP1 −/− dogs lacking obvious clinical signs. Phenotypic variation has been known in human homologous diseases, including retinitis pigmentosa and Leber congenital amaurosis, indicating possible involvement of modifiers. To explore additional genetic loci associated with the phenotypic variation observed in MLHDs, a genome-wide association study was carried out using Canine SNP20 arrays in 83 RPGRIP1 −/− MLHDs with variable ages of onset or no clinical abnormality. Using these samples, comparison of 31 early-onset RD cases against 49 controls (15 late-onset RD and 34 normal dogs combined) identified a strong association (P = 5.05 × 10−13) at a single locus on canine chromosome 15. At this locus, the majority of early-onset RD cases but few of the controls were homozygous for a 1.49 Mb interval containing ~11 genes. We conclude that homozygosity at both RPGRIP1 and the newly mapped second locus is necessary to develop early-onset RD, whereas RPGRIP1 −/− alone leads to late-onset RD or no apparent clinical phenotype. This study establishes a unique model of canine RD requiring homozygous mutations at two distinct genetic loci for the manifestation of early-onset RD.

  • phenotypic variation and genotype phenotype discordance in canine cone rod dystrophy with an rpgrip1 mutation
    Molecular Vision, 2009
    Co-Authors: Keiko Miyadera, N G Holmes, Keith C Barnett, Claudia Busse, Kumiko Kato, Jesus Aguirrehernandez, Tsuyoshi Tokuriki, Kyohei Morimoto, Hiroyuki Ogawa, Nobuo Sasaki
    Abstract:

    Purpose: Previously, a 44 bp insertion in exon 2 of retinitis pigmentosa GTPase interacting protein 1 (RPGRIP1) was identified as the cause of cone-rod dystrophy 1 (cord1), a recessive form of progressive retinal atrophy (PRA) in the Miniature Longhaired Dachshund (MLHD), a dog model for Leber congenital amaurosis. The cord1 locus was mapped using MLHDs from an inbred colony with a homogeneous early onset disease phenotype. In this paper, the MLHD pet population was studied to investigate phenotypic variation and genotype-phenotype correlation. Further, the cord1 locus was fine-mapped using PRA cases from the MLHD pet population to narrow the critical region. Other dog breeds were also screened for the RGPRIP1 insertion. Methods: This study examined phenotypic variation in an MLHD pet population that included 59 sporadic PRA cases and 18 members of an extended family with shared environment and having six PRA cases. Ophthalmologic evaluations included behavioral abnormalities, responses to menace and light, fundoscopy, and electroretinography (ERG). The RPGRIP1 insertion was screened for in all cases and 200 apparently normal control MLHDs and in 510 dogs from 66 other breed. To fine-map the cord1 locus in the MLHD, 74 PRA cases and 86 controls aged 4 years or more were genotyped for 24 polymorphic markers within the previously mapped cord1 critical region of 14.15 Mb. Results: Among sporadic PRA cases from the MLHD pet population, the age of onset varied from 4 months to 15 years old; MLHDs from the extended family also showed variable onset and rate of progression. Screening for the insertion in RPGRIP1 identified substantial genotype-phenotype discordance: 16% of controls were homozygous for the insertion (RPGRIP1−/−), while 20% of PRA cases were not homozygous for it. Four other breeds were identified to carry the insertion including English Springer Spaniels and Beagles with insertion homozygotes. The former breed included both controls and PRA cases, yet in the latter breed, cone ERG was undetectable in two dogs with no clinically apparent visual dysfunction. Notably, the insertion in the Beagles was a longer variant of that seen in the other breeds. Fine-mapping of the cord1 locus narrowed the critical region on CFA15 from 14.15 Mb to 1.74 Mb which still contains the RPGRIP1 gene. Conclusions: Extensive phenotypic variations of onset age and progression rate were observed in PRA cases of the MLHD pet population. The insertion in RPGRIP1 showed the strongest association with the disease, yet additional as well as alternative factors may account for the substantial genotype-phenotype discordance.

Christine Vesque - One of the best experts on this subject based on the ideXlab platform.

  • RPGRIP1L controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone
    Molecular Biology of the Cell, 2021
    Co-Authors: Antonia Wiegering, Sylvie Schneider-maunoury, Hemant Khanna, Christine Vesque, Renate Dildrop, Christoph Gerhardt
    Abstract:

    A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein RPGRIP1L governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of RPGRIP1L.

  • RPGRIP1L controls ciliary gating by ensuring the proper amount of cep290 at the vertebrate transition zone
    Molecular Biology of the Cell, 2021
    Co-Authors: Hemant Khanna, Antonia Wiegering, Christine Vesque, Sylvie Schneidermaunoury, Renate Dildrop, Christoph Gerhardt
    Abstract:

    The study provided by Wiegering et al. investigates molecular mechanisms underlying ciliary entry and exit of proteins. It demonstrates that RPGRIP1L governs ciliary gating by controlling the amoun...

  • MKS-NPHP module proteins control ciliary shedding at the transition zone
    PLoS biology, 2020
    Co-Authors: Delphine Gogendeau, Sylvie Schneider-maunoury, Michel Lemullois, Pierrick Le Borgne, Manon Castelli, Anne Aubusson-fleury, Olivier Arnaiz, Jean Cohen, Christine Vesque, Khaled Bouhouche
    Abstract:

    Ciliary shedding occurs from unicellular organisms to metazoans. Although required during the cell cycle and during neurogenesis, the process remains poorly understood. In all cellular models, this phenomenon occurs distal to the transition zone (TZ), suggesting conserved molecular mechanisms. The TZ module proteins (Meckel Gruber syndrome [MKS]/Nephronophtysis [NPHP]/Centrosomal protein of 290 kDa [CEP290]/Retinitis pigmentosa GTPase regulator-Interacting Protein 1-Like Protein [RPGRIP1L]) are known to cooperate to establish TZ formation and function. To determine whether they control deciliation, we studied the function of 5 of them (Transmembrane protein 107 [TMEM107], Transmembrane protein 216 [TMEM216], CEP290, RPGRIP1L, and NPHP4) in Paramecium. All proteins are recruited to the TZ of growing cilia and localize with 9-fold symmetry at the level of the most distal part of the TZ. We demonstrate that depletion of the MKS2/TMEM216 and TMEM107 proteins induces constant deciliation of some cilia, while depletion of either NPHP4, CEP290, or RPGRIP1L prevents Ca2+/EtOH deciliation. Our results constitute the first evidence for a role of conserved TZ proteins in deciliation and open new directions for understanding motile cilia physiology.

  • loss of the reissner fiber and increased urp neuropeptide signaling underlie scoliosis in a zebrafish ciliopathy mutant
    bioRxiv, 2019
    Co-Authors: Christine Vesque, Isabelle Anselme, Guillaume Pezeron, Yasmine Cantautbelarif, Alexis Eschstruth, Morgane Djebar, Diego Lopezsantos, Helene Le Ribeuz, Arnim Jenett, Hanane Khoury
    Abstract:

    Cilia-driven movements of the cerebrospinal fluid (CSF) are involved in zebrafish axis straightness, both in embryos and juveniles [1, 2]. In embryos, axis straightness requires ciliadependent assembly of the Reissner fiber (RF), a SCO-spondin polymer running down the brain and spinal cord CSF-filled cavities [3]. Reduced expression levels of the urp1 and urp2 genes encoding neuropeptides of the Urotensin II family in CSF-contacting neurons (CSF-cNs) also underlie embryonic ventral curvature of several cilia motility mutants [4]. Moreover, mutants for scospondin and uts2r3 (a Urotensin II peptide family receptor gene) develop scoliosis at juvenile stages [3, 4]. However, whether RF maintenance and URP signaling are perturbed in juvenile scoliotic ciliary mutants and how these perturbations are linked to scoliosis is unknown. Here we produced mutants in the zebrafish ortholog of the human RPGRIP1L ciliopathy gene encoding a transition zone protein [5-7]. RPGRIP1L-/- zebrafish had normal embryogenesis and developed 3D spine torsions in juveniles. Cilia lining the CNS cavities were normal in RPGRIP1L-/- embryos but sparse and malformed in juveniles and adults. Hindbrain ventricle dilations were present at scoliosis onset, suggesting defects in CSF flow. Immunostaining showed a secondary loss of RF correlating with juvenile scoliosis. Surprisingly, transcriptome analysis of rgprip1l mutants at scoliosis onset uncovered increased levels of urp1 and urp2 expression. Overexpressing urp2 in foxj1-expressing cells triggered scoliosis in RPGRIP1L heterozygotes. Thus, our results demonstrate that increased URP signaling drives scoliosis onset in a ciliopathy mutant. We propose that imbalanced levels of URP neuropeptides in CSF-cNs may be an initial trigger of scoliosis.

  • Functional analysis of the transition zone protein RPGRIP1L during zebrafish development
    Cilia, 2012
    Co-Authors: Christine Vesque, Alexia Mahuzier, Isabelle Anselme, M Leroux-berger, Sylvie Schneider-maunoury
    Abstract:

    We investigated the function of RPGRIP1L during zebrafish development. RPGRIP1L encodes a protein localised at the ciliary transition zone and interacts functionally with NPH and MKS for the formation and function of the ciliary gate. The human RPGRIP1L gene is a causal gene in Meckel and Joubert type B syndromes, characterised by polydactyly, kidney cysts and central nervous system malformations. Using morpholinos injection, we show that loss of RPGRIP1L function leads to several early phenotypes such as convergent-extension phenotype, randomisation of left-right asymmetry and hydrocephaly. We focussed our study on the Wnt-PCP defects and we demonstrated that in the zebrafish floorplate, RPGRIP1L is required for correct positioning of the basal body along the planar polarity axis. We confirmed RPGRIP1L function on basal body positioning in the mechanosensory hair cells of the cochlea of the murine mutant for RPGRIP1L. Our results strongly suggest that RPGRIP1L is essential for recruiting and stabilizing dishevelled, a major actor of the PCP pathway, at the basal body and/or cilium. Indeed, in two different cell types, in the zebrafish floor plate and in the murine cochlea, dishevelled proteins are enriched at the cilium and/or basal body, and this localization is severely perturbed upon RPGRIP1L depletion. Finally, we demonstrate that, in the zebrafish floor plate, the function of RPGRIP1L in basal body positioning is mediated by dishevelled. We propose that RPGRIP1L participates in a protein complex required for recruiting and stabilizing dishevelled at the cilium, a process essential for planar polarization of the basal body.

Sylvie Schneider-maunoury - One of the best experts on this subject based on the ideXlab platform.

  • RPGRIP1L controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone
    Molecular Biology of the Cell, 2021
    Co-Authors: Antonia Wiegering, Sylvie Schneider-maunoury, Hemant Khanna, Christine Vesque, Renate Dildrop, Christoph Gerhardt
    Abstract:

    A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein RPGRIP1L governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of RPGRIP1L.

  • MKS-NPHP module proteins control ciliary shedding at the transition zone
    PLoS biology, 2020
    Co-Authors: Delphine Gogendeau, Sylvie Schneider-maunoury, Michel Lemullois, Pierrick Le Borgne, Manon Castelli, Anne Aubusson-fleury, Olivier Arnaiz, Jean Cohen, Christine Vesque, Khaled Bouhouche
    Abstract:

    Ciliary shedding occurs from unicellular organisms to metazoans. Although required during the cell cycle and during neurogenesis, the process remains poorly understood. In all cellular models, this phenomenon occurs distal to the transition zone (TZ), suggesting conserved molecular mechanisms. The TZ module proteins (Meckel Gruber syndrome [MKS]/Nephronophtysis [NPHP]/Centrosomal protein of 290 kDa [CEP290]/Retinitis pigmentosa GTPase regulator-Interacting Protein 1-Like Protein [RPGRIP1L]) are known to cooperate to establish TZ formation and function. To determine whether they control deciliation, we studied the function of 5 of them (Transmembrane protein 107 [TMEM107], Transmembrane protein 216 [TMEM216], CEP290, RPGRIP1L, and NPHP4) in Paramecium. All proteins are recruited to the TZ of growing cilia and localize with 9-fold symmetry at the level of the most distal part of the TZ. We demonstrate that depletion of the MKS2/TMEM216 and TMEM107 proteins induces constant deciliation of some cilia, while depletion of either NPHP4, CEP290, or RPGRIP1L prevents Ca2+/EtOH deciliation. Our results constitute the first evidence for a role of conserved TZ proteins in deciliation and open new directions for understanding motile cilia physiology.

  • RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis
    PLoS Genetics, 2019
    Co-Authors: Yeon Ja Choi, Christine Laclef, Ning Yang, Abraham Andreu-cervera, Joshua Lewis, Xuming Mao, Elizabeth Snedecor, Ken-ichi Takemaru, Chuan Qin, Sylvie Schneider-maunoury
    Abstract:

    Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in the maintenance of desmosomal junctions between keratinocytes. Genetically disrupting the RPGRIP1L gene in mice caused intraepidermal blistering, primarily between basal and suprabasal keratinocytes. This blistering phenotype was associated with aberrant expression patterns of desmosomal proteins, impaired desmosome ultrastructure, and compromised cell-cell adhesion in vivo and in vitro. We found that disrupting the RPGRIP1L gene in HaCaT cells, which do not form primary cilia, resulted in mislocalization of desmosomal proteins to the cytoplasm, suggesting a cilia-independent function of RPGRIP1L. Mechanistically, we found that RPGRIP1L regulates the endocytosis of desmogleins such that RPGRIP1L-knockdown not only induced spontaneous desmoglein endocytosis, as determined by AK23 labeling and biotinylation assays, but also exacerbated EGTA- or pemphigus vulgaris IgG-induced desmoglein endocytosis. Accordingly, inhibiting endocytosis with dynasore or sucrose rescued these desmosomal phenotypes. Biotinylation assays on cell surface proteins not only reinforced the role of RPGRIP1L in desmoglein endocytosis, but also suggested that RPGRIP1L may be more broadly involved in endocytosis. Thus, data obtained from this study advanced our understanding of the biological functions of RPGRIP1L by identifying its role in the cellular endocytic pathway.

  • The Ciliopathy Gene RPGRIP1L Is Essential for Hair Follicle Development
    Journal of Investigative Dermatology, 2015
    Co-Authors: Jiang Chen, Christine Laclef, Ning Yang, Elizabeth Snedecor, Ken-ichi Takemaru, Sylvie Schneider-maunoury, Alejandra Moncayo, Ralf Paus, Richard A. Clark
    Abstract:

    The primary cilium is essential for skin morphogenesis through regulating the Notch, Wnt, and hedgehog signaling pathways. Prior studies on the functions of primary cilia in the skin were based on the investigations of genes that are essential for cilium formation. However, none of these ciliogenic genes has been linked to ciliopathy, a group of disorders caused by abnormal formation or function of cilia. To determine whether there is a genetic and molecular link between ciliopathies and skin morphogenesis, we investigated the role of RPGRIP1L, a gene mutated in Joubert (JBTS) and Meckel (MKS) syndromes, two severe forms of ciliopathy, in the context of skin development. We found that RPGRIP1L is essential for hair follicle morphogenesis. Specifically, disrupting the RPGRIP1L gene in mice resulted in reduced proliferation and differentiation of follicular keratinocytes, leading to hair follicle developmental defects. These defects were associated with significantly decreased primary cilium formation and attenuated hedgehog signaling. In contrast, we found that hair follicle induction and polarization and the development of interfollicular epidermis were unaffected. This study indicates that RPGRIP1L, a ciliopathy gene, is essential for hair follicle morphogenesis likely through regulating primary cilia formation and the hedgehog signaling pathway.

  • Functional analysis of the transition zone protein RPGRIP1L during zebrafish development
    Cilia, 2012
    Co-Authors: Christine Vesque, Alexia Mahuzier, Isabelle Anselme, M Leroux-berger, Sylvie Schneider-maunoury
    Abstract:

    We investigated the function of RPGRIP1L during zebrafish development. RPGRIP1L encodes a protein localised at the ciliary transition zone and interacts functionally with NPH and MKS for the formation and function of the ciliary gate. The human RPGRIP1L gene is a causal gene in Meckel and Joubert type B syndromes, characterised by polydactyly, kidney cysts and central nervous system malformations. Using morpholinos injection, we show that loss of RPGRIP1L function leads to several early phenotypes such as convergent-extension phenotype, randomisation of left-right asymmetry and hydrocephaly. We focussed our study on the Wnt-PCP defects and we demonstrated that in the zebrafish floorplate, RPGRIP1L is required for correct positioning of the basal body along the planar polarity axis. We confirmed RPGRIP1L function on basal body positioning in the mechanosensory hair cells of the cochlea of the murine mutant for RPGRIP1L. Our results strongly suggest that RPGRIP1L is essential for recruiting and stabilizing dishevelled, a major actor of the PCP pathway, at the basal body and/or cilium. Indeed, in two different cell types, in the zebrafish floor plate and in the murine cochlea, dishevelled proteins are enriched at the cilium and/or basal body, and this localization is severely perturbed upon RPGRIP1L depletion. Finally, we demonstrate that, in the zebrafish floor plate, the function of RPGRIP1L in basal body positioning is mediated by dishevelled. We propose that RPGRIP1L participates in a protein complex required for recruiting and stabilizing dishevelled at the cilium, a process essential for planar polarization of the basal body.

Christoph Gerhardt - One of the best experts on this subject based on the ideXlab platform.

  • RPGRIP1L controls ciliary gating by ensuring the proper amount of Cep290 at the vertebrate transition zone
    Molecular Biology of the Cell, 2021
    Co-Authors: Antonia Wiegering, Sylvie Schneider-maunoury, Hemant Khanna, Christine Vesque, Renate Dildrop, Christoph Gerhardt
    Abstract:

    A range of severe human diseases called ciliopathies are caused by the dysfunction of primary cilia. Primary cilia are cytoplasmic protrusions consisting of the basal body (BB), the axoneme and the transition zone (TZ). The BB is a modified mother centriole from which the axoneme, the microtubule-based ciliary scaffold, is formed. At the proximal end of the axoneme, the TZ functions as the ciliary gate governing ciliary protein entry and exit. Since ciliopathies often develop due to mutations in genes encoding proteins that localise to the TZ, the understanding of the mechanisms underlying TZ function is of eminent importance. Here, we show that the ciliopathy protein RPGRIP1L governs ciliary gating by ensuring the proper amount of Cep290 at the vertebrate TZ. Further, we identified the flavonoid eupatilin as a potential agent to tackle ciliopathies caused by mutations in RPGRIP1L as it rescues ciliary gating in the absence of RPGRIP1L.

  • RPGRIP1L controls ciliary gating by ensuring the proper amount of cep290 at the vertebrate transition zone
    Molecular Biology of the Cell, 2021
    Co-Authors: Hemant Khanna, Antonia Wiegering, Christine Vesque, Sylvie Schneidermaunoury, Renate Dildrop, Christoph Gerhardt
    Abstract:

    The study provided by Wiegering et al. investigates molecular mechanisms underlying ciliary entry and exit of proteins. It demonstrates that RPGRIP1L governs ciliary gating by controlling the amoun...

  • the ciliary protein RPGRIP1L in development and disease
    Developmental Biology, 2018
    Co-Authors: Antonia Wiegering, Ulrich Ruther, Christoph Gerhardt
    Abstract:

    RPGRIP1L is an evolutionary highly conserved gene encoding a protein that localises at the transition zone of primary cilia. Mutations in RPGRIP1L result in ciliopathies, severe human diseases caused by dysfunctional cilia. Patients with mutations in this gene often suffer from an impaired development of not only one but various organs. To elucidate the function of RPGRIP1L in human development and the mechanisms underlying ciliopathies, different model organisms are used. In this review article, we summarise the findings of these investigations comprising novel functions of RPGRIP1L and the most promising therapeutic approaches.

  • The ciliary protein RPGRIP1L governs autophagy independently of its proteasome-regulating function at the ciliary base in mouse embryonic fibroblasts
    2018
    Co-Authors: Andreas Struchtrup, Ulrich Ruther, Antonia Wiegering, Björn Stork, Christoph Gerhardt
    Abstract:

    Previously, macroautophagy/autophagy was demonstrated to be regulated inter alia by the primary cilium. Mutations in RPGRIP1L cause ciliary dysfunctions resulting in severe human diseases summarized as ciliopathies. Recently, we showed that RPGRIP1L deficiency leads to a decreased proteasomal activity at the ciliary base in mice. Importantly, the drug-induced restoration of proteasomal activity does not rescue ciliary length alterations in the absence of RPGRIP1L indicating that RPGRIP1L affects ciliary function also via other mechanisms. Based on this knowledge, we analyzed autophagy in RPGRIP1L-negative mouse embryos. In these embryos, autophagic activity was decreased due to an increased activation of the MTOR complex 1 (MTORC1). Application of the MTORC1 inhibitor rapamycin rescued dysregulated MTORC1, autophagic activity and cilia length but not proteasomal activity in RPGRIP1L-deficient mouse embryonic fibroblasts demonstrating that RPGRIP1L seems to regulate autophagic and proteasomal activity independently from each other.

  • the transition zone protein RPGRIP1L regulates proteasomal activity at the primary cilium
    Journal of Cell Biology, 2015
    Co-Authors: Christoph Gerhardt, Johanna Maria Lier, Stephan Burmuhl, Andreas Struchtrup, K Deutschmann, Maik Vetter, Tristan Leu, Sandra Reeg, Tilman Grune, Ulrich Ruther
    Abstract:

    Mutations in RPGRIP1L result in severe human diseases called ciliopathies. To unravel the molecular function of RPGRIP1L, we analyzed RPGRIP1L−/− mouse embryos, which display a ciliopathy phenotype and die, at the latest, around birth. In these embryos, cilia-mediated signaling was severely disturbed. Defects in Shh signaling suggested that the RPGRIP1L deficiency causes an impairment of protein degradation and protein processing. Indeed, we detected a cilia-dependent decreased proteasomal activity in the absence of RPGRIP1L. We found different proteasomal components localized to cilia and identified Psmd2, a component of the regulatory proteasomal 19S subunit, as an interaction partner for RPGRIP1L. Quantifications of proteasomal substrates demonstrated that RPGRIP1L regulates proteasomal activity specifically at the basal body. Our study suggests that RPGRIP1L controls ciliary signaling by regulating the activity of the ciliary proteasome via Psmd2.

Related terms

RPGRIP1L - 15 days free trial to Access Experts & Abstracts