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Jean Cohen - One of the best experts on this subject based on the ideXlab platform.
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paramecium tetraurelia Basal Body unit isolation for cryo electron tomography studies
Cilia, 2015Co-Authors: Janine Beisson, Michel Lemullois, A Aubussonfleury, Jean Cohen, S Trepout, Paul Guichard, F Koll, Sergio MarcoAbstract:Objective The Transition Zone (TZ) is defined as the most proximal region of the cilium overlapping with the most distal region of the Basal Body. This zone has been shown to play a crucial role in cilia biology since it is considered as the site of sorting of proteins that transit to cilia. Protein complexes housed at this zone are found mutated in MKS/NPHP ciliopathies. Although its organization varies from organism to organism, the TZ molecular composition and function are highly conserved. In Paramecium, the TZ is well structured with three distinct plates defined as the terminal, the intermediate and the axosomal plates. In this model, structural and molecular changes of the TZ are observed as anchored Basal bodies become ciliated. Therefore, Paramecium appears to be a pertinent model to study the TZ at an ultrastructural level in correlation with its functionality.
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the conserved centrosomal protein for20 is required for assembly of the transition zone and Basal Body docking at the cell surface
Journal of Cell Science, 2012Co-Authors: Nicole Garreau De Loubresse, Michel Lemullois, A Aubussonfleury, Chloe Laligne, Jean CohenAbstract:Summary Within the FOP family of centrosomal proteins, the conserved FOR20 protein has been implicated in the control of primary cilium assembly in human cells. To ascertain its role in ciliogenesis, we have investigated the function of its ortholog, PtFOR20p, in the multiciliated unicellular organism Paramecium . Using combined functional and cytological analyses, we found that PtFOR20p specifically localises at Basal bodies and is required to build the transition zone, a prerequisite to their maturation and docking at the cell surface and hence to ciliogenesis. We also found that PtCen2p (one of the two Basal Body specific centrins, an ortholog of HsCen2) is required to recruit PtFOR20p at the developing Basal Body and to control its length. By contrast, the other Basal-Body-specific centrin PtCen3p is not needed for assembly of the transition zone, but is required downstream, for Basal Body docking. Comparison of the structural defects induced by depletion of PtFOR20p, PtCen2p or PtCen3p, respectively, illustrates the dual role of the transition zone in the biogenesis of the Basal Body and in cilium assembly. The multiple potential roles of the transition zone during Basal Body biogenesis and the evolutionary conserved function of the FOP proteins in microtubule membrane interactions are discussed.
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sas 4 proteins are required during Basal Body duplication in paramecium
Molecular Biology of the Cell, 2011Co-Authors: Delphine Gogendeau, Jean Cohen, Ilse Hurbain, Graca Raposo, Renata BastoAbstract:Centrioles and Basal bodies are structurally related organelles composed of nine microtubule (MT) triplets. Studies performed in Caenorhabditis elegans embryos have shown that centriole duplication takes place in sequential way, in which different proteins are recruited in a specific order to assemble a procentriole. ZYG-1 initiates centriole duplication by triggering the recruitment of a complex of SAS-5 and SAS-6, which then recruits the final player, SAS-4, to allow the incorporation of MT singlets. It is thought that a similar mechanism (that also involves additional proteins) is present in other animal cells, but it remains to be investigated whether the same players and their ascribed functions are conserved during Basal Body duplication in cells that exclusively contain Basal bodies. To investigate this question, we have used the multiciliated protist Paramecium tetraurelia. Here we show that in the absence of PtSas4, two types of defects in Basal Body duplication can be identified. In the majority of cases, the germinative disk and cartwheel, the first structures assembled during duplication, are not detected. In addition, if daughter Basal bodies were formed, they invariably had defects in MT recruitment. Our results suggest that PtSas4 has a broader function than its animal orthologues.
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Basal Body duplication in paramecium the key role of bld10 in assembly and stability of the cartwheel
Cytoskeleton, 2010Co-Authors: Maria Jerkadziadosz, Janine Beisson, Catherine Klotz, Delphine Gogendeau, Jean CohenAbstract:Basal bodies which nucleate cilia and flagella, and centrioles which organize centrosomes share the same architecture characterized by the ninefold symmetry of their microtubular shaft. Among the conserved proteins involved in the biogenesis of the canonical 9-triplet centriolar structures, Sas-6 and Bld10 proteins have been shown to play central roles in the early steps of assembly and in establishment/stabilization of the ninefold symmetry. Using fluorescent tagged proteins and RNAi to study the localization and function of these two proteins in Paramecium, we focused on the early effects of their depletion, the consequences of their overexpression and their functional interdependence. We find that both genes are essential and their depletion affects cartwheel assembly and hence Basal Body duplication. We also show that, contrary to Sas6p, Bld10p is not directly responsible for the establishment of the ninefold symmetry, but is required not only for new Basal Body assembly and stability but also for Sas6p maintenance at mature Basal bodies. Finally, ultrastructural analysis of cells overexpressing either protein revealed two types of early assembly intermediates, hub-like structures and generative discs, suggesting a conserved scaffolding process. © 2010 Wiley-Liss, Inc.
Michio Homma - One of the best experts on this subject based on the ideXlab platform.
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role of the n and c terminal regions of flif the ms ring component in vibrio flagellar Basal Body
bioRxiv, 2021Co-Authors: Seiji Kojima, Hiroyuki Terashima, Hiroki Kajino, Keiichi Hirano, Yuna Inoue, Michio HommaAbstract:The MS ring is a part of the flagellar Basal Body and formed by 34 subunits of FliF, which consists of a large periplasmic region and two transmembrane segments connected to the N- and C-terminal regions facing the cytoplasm. A cytoplasmic protein, FlhF, which determines the position and number of the Basal Body, supports MS ring formation in the membrane. In this study, we constructed FliF deletion mutants that lack 30 or 50 residues at the N-terminus (ΔN30 and ΔN50), and 83 (ΔC83) or 110 residues (ΔC110) at the C-terminus. The N-terminal deletions were functional and conferred motility of Vibrio cells, whereas the C-terminal deletions were nonfunctional. The mutants were expressed in Escherichia coli to determine whether an MS ring could still be assembled. When co-expressing ΔN30FliF or ΔN50FliF with FlhF, fewer MS rings were observed than with the expression of wild-type FliF, in the MS ring fraction, suggesting that the N-terminus interacts with FlhF. MS ring formation is probably inefficient without an additional factor or FlhF. The deletion of the C-terminal cytoplasmic region did not affect the ability of FliF to form an MS ring because a similar number of MS rings were observed for ΔC83FliF as with wild-type FliF, although further deletion of the second transmembrane segment (ΔC110FliF) abolished it. These results suggest that the terminal regions of FliF have distinct roles; the N-terminal region for efficient MS ring formation and the C-terminal region for MS ring function. The second transmembrane segment is indispensable for MS ring assembly.
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the vibrio motor proteins motx and moty are associated with the Basal Body of na driven flagella and required for stator formation
Molecular Microbiology, 2006Co-Authors: Hiroyuki Terashima, Hajime Fukuoka, Toshiharu Yakushi, Seiji Kojima, Michio HommaAbstract:The four motor proteins PomA, PomB, MotX and MotY, which are believed to be stator proteins, are essential for motility by the Na(+)-driven flagella of Vibrio alginolyticus. When we purified the flagellar Basal bodies, MotX and MotY were detected in the Basal Body, which is the supramolecular complex comprised of the rotor and the bushing, but PomA and PomB were not. By antiBody labelling, MotX and MotY were detected around the LP ring. These results indicate that MotX and MotY associate with the Basal Body. The Basal Body had a new ring structure beneath the LP ring, which was named the T ring. This structure was changed or lost in the Basal Body from a DeltamotX or DeltamotY strain. The T ring probably comprises MotX and MotY. In the absence of MotX or MotY, we demonstrated that PomA and PomB were not localized to a cell pole. From the above results, we suggest that MotX and MotY of the T ring are involved in the incorporation and/or stabilization of the PomA/PomB complex in the motor.
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the vibrio motor proteins motx and moty are associated with the Basal Body of na driven flagella and required for stator formation
Molecular Microbiology, 2006Co-Authors: Hiroyuki Terashima, Hajime Fukuoka, Toshiharu Yakushi, Seiji Kojima, Michio HommaAbstract:Summary The four motor proteins PomA, PomB, MotX and MotY, which are believed to be stator proteins, are essential for motility by the Na + -driven flagella of Vibrio alginolyticus. When we purified the flagellar Basal bodies, MotX and MotY were detected in the Basal Body, which is the supramolecular complex comprised of the rotor and the bushing, but PomA and PomB were not. By antiBody labelling, MotX and MotY were detected around the LP ring. These results indicate that MotX and MotY associate with the Basal Body. The Basal Body had a new ring structure beneath the LP ring, which was named the T ring. This structure was changed or lost in the Basal Body from a DmotX or DmotY strain. The T ring probably com- prises MotX and MotY. In the absence of MotX or MotY, we demonstrated that PomA and PomB were not localized to a cell pole. From the above results, we suggest that MotX and MotY of the T ring are involved in the incorporation and/or stabilization of the PomA/ PomB complex in the motor.
Colin A. Johnson - One of the best experts on this subject based on the ideXlab platform.
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The Meckel-Gruber Syndrome protein TMEM67 (meckelin) regulates Basal Body planar polarization and non-canonical Wnt signalling via Wnt5a and ROR2
Cilia, 2015Co-Authors: Zakia Abdelhamed, Subaashini Natarajan, C. F. Inglehearn, Carmel Toomes, Colin A. JohnsonAbstract:Results: Tmem67 mutant phenotypes include pulmonary hypoplasia, ventricular septal defects, shortening of the Body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and Basal Body/ kinocilium positioning defects. The Basal Body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant Basal Body migration. TMEM67 (meckelin) is essential for phosphorylation of the noncanonical Wnt receptor ROR2 (receptor tyrosine kinaselike orphan receptor 2) upon Wnt5a stimulation. ROR2 interacts with the intracellular C-terminal domain of TMEM67 and co-localizes with TMEM67 at the ciliary transition zone. The N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Tmem67 mutant embryonic lungs in ex vivo culture failed to respond to Wnt5a stimulation of epithelial morphogenesis. However, stimulating the non-canonical Wnt pathway downstream of the receptor by activating RhoA resulted in an elicited response and the rescue of lung hypoplasia phenotypes.
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the meckel gruber syndrome protein tmem67 controls Basal Body positioning and epithelial branching morphogenesis in mice via the non canonical wnt pathway
Disease Models & Mechanisms, 2015Co-Authors: Zakia Abdelhamed, Subaashini Natarajan, C. F. Inglehearn, Carmel Toomes, Gabrielle Wheway, Colin A. JohnsonAbstract:Ciliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the Body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and Basal Body/kinocilium positioning defects. The Basal Body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant Basal Body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions.
Michel Lemullois - One of the best experts on this subject based on the ideXlab platform.
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Basal Body positioning and anchoring in the multiciliated cell paramecium tetraurelia roles of ofd1 and vfl3
Cilia, 2017Co-Authors: Hakim Bengueddach, Michel Lemullois, Anne AubussonfleuryAbstract:The development of a ciliary axoneme requires the correct docking of the Basal Body at cytoplasmic vesicles or plasma membrane. In the multiciliated cell Paramecium, three conserved proteins, FOR20, Centrin 2, and Centrin 3 participate in this process, FOR20 and Centrin 2 being involved in the assembly of the transition zone. We investigated the function of two other evolutionary conserved proteins, OFD1 and VFL3, likely involved in this process. In Paramecium tetraurelia, a single gene encodes OFD1, while four genes encode four isoforms of VFL3, grouped into two families, VFL3-A and VFL3-B. Depletion of OFD1 and the sole VFL3-A family impairs Basal Body docking. Loss of OFD1 yields a defective assembly of the Basal Body distal part. Like FOR20, OFD1 is recruited early during Basal Body assembly and localizes at the transition zone between axoneme and membrane at the level of the microtubule doublets. While the recruitment of OFD1 and Centrin 2 proceed independently, the localizations of OFD1 and FOR20 at the Basal Body are interdependent. In contrast, in VFL3-A depleted cells, the unanchored Basal bodies harbor a fully organized distal part but display an abnormal distribution of their associated rootlets which mark their rotational asymmetry. VFL3-A, which is required for the recruitment of Centrin 3, is transiently present near the Basal bodies at an early step of their duplication. VFL3-A localizes at the junction between the striated rootlet and the Basal Body. Our results demonstrate the conserved role of OFD1 in the anchoring mechanisms of motile cilia and establish its relations with FOR20 and Centrin 2. They support the hypothesis of its association with microtubule doublets. They suggest that the primary defect of VFL3 depletion is a loss of the rotational asymmetry of the Basal Body which specifies the sites of assembly of the appendages which guide the movement of Basal bodies toward the cell surface. The localization of VFL3 outside of the Basal Body suggests that extrinsic factors could control this asymmetry.
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Basal Body positioning and anchoring in the multiciliated cell Paramecium tetraurelia: roles of OFD1 and VFL3
BMC, 2017Co-Authors: Hakim Bengueddach, Michel Lemullois, Anne Aubusson-fleury, France KollAbstract:Abstract Background The development of a ciliary axoneme requires the correct docking of the Basal Body at cytoplasmic vesicles or plasma membrane. In the multiciliated cell Paramecium, three conserved proteins, FOR20, Centrin 2, and Centrin 3 participate in this process, FOR20 and Centrin 2 being involved in the assembly of the transition zone. We investigated the function of two other evolutionary conserved proteins, OFD1 and VFL3, likely involved in this process. Results In Paramecium tetraurelia, a single gene encodes OFD1, while four genes encode four isoforms of VFL3, grouped into two families, VFL3-A and VFL3-B. Depletion of OFD1 and the sole VFL3-A family impairs Basal Body docking. Loss of OFD1 yields a defective assembly of the Basal Body distal part. Like FOR20, OFD1 is recruited early during Basal Body assembly and localizes at the transition zone between axoneme and membrane at the level of the microtubule doublets. While the recruitment of OFD1 and Centrin 2 proceed independently, the localizations of OFD1 and FOR20 at the Basal Body are interdependent. In contrast, in VFL3-A depleted cells, the unanchored Basal bodies harbor a fully organized distal part but display an abnormal distribution of their associated rootlets which mark their rotational asymmetry. VFL3-A, which is required for the recruitment of Centrin 3, is transiently present near the Basal bodies at an early step of their duplication. VFL3-A localizes at the junction between the striated rootlet and the Basal Body. Conclusion Our results demonstrate the conserved role of OFD1 in the anchoring mechanisms of motile cilia and establish its relations with FOR20 and Centrin 2. They support the hypothesis of its association with microtubule doublets. They suggest that the primary defect of VFL3 depletion is a loss of the rotational asymmetry of the Basal Body which specifies the sites of assembly of the appendages which guide the movement of Basal bodies toward the cell surface. The localization of VFL3 outside of the Basal Body suggests that extrinsic factors could control this asymmetry
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paramecium tetraurelia Basal Body unit isolation for cryo electron tomography studies
Cilia, 2015Co-Authors: Janine Beisson, Michel Lemullois, A Aubussonfleury, Jean Cohen, S Trepout, Paul Guichard, F Koll, Sergio MarcoAbstract:Objective The Transition Zone (TZ) is defined as the most proximal region of the cilium overlapping with the most distal region of the Basal Body. This zone has been shown to play a crucial role in cilia biology since it is considered as the site of sorting of proteins that transit to cilia. Protein complexes housed at this zone are found mutated in MKS/NPHP ciliopathies. Although its organization varies from organism to organism, the TZ molecular composition and function are highly conserved. In Paramecium, the TZ is well structured with three distinct plates defined as the terminal, the intermediate and the axosomal plates. In this model, structural and molecular changes of the TZ are observed as anchored Basal bodies become ciliated. Therefore, Paramecium appears to be a pertinent model to study the TZ at an ultrastructural level in correlation with its functionality.
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paramecium tetraurelia Basal Body structure
Cilia, 2015Co-Authors: Annemarie Tassin, Michel Lemullois, Anne AubussonfleuryAbstract:Paramecium is a free-living unicellular organism, easy to cultivate, featuring ca. 4000 motile cilia emanating from longitudinal rows of Basal bodies anchored in the plasma membrane. The Basal Body circumferential polarity is marked by the asymmetrical organization of its associated appendages. The complex Basal Body plus its associated rootlets forms the kinetid. Kinetids are precisely oriented within a row in correlation with the cell polarity. Basal bodies also display a proximo-distal polarity with microtubule triplets at their proximal ends, surrounding a permanent cartwheel, and microtubule doublets at the transition zone located between the Basal Body and the cilium. Basal bodies remain anchored at the cell surface during the whole cell cycle. On the opposite to metazoan, there is no centriolar stage and new Basal bodies develop anteriorly and at right angle from the base of the docked ones. Ciliogenesis follows a specific temporal pattern during the cell cycle and both unciliated and ciliated docked Basal bodies can be observed in the same cell. The transition zone is particularly well organized with three distinct plates and a maturation of its structure is observed during the growth of the cilium. Transcriptomic and proteomic analyses have been performed in different organisms including Paramecium to understand the ciliogenesis process. The data have incremented a multi-organism database, dedicated to proteins involved in the biogenesis, composition and function of centrosomes, Basal bodies or cilia. Thanks to its thousands of Basal bodies and the well-known choreography of their duplication during the cell cycle, Paramecium has allowed pioneer studies focusing on the structural and functional processes underlying Basal Body duplication. Proteins involved in Basal Body anchoring are sequentially recruited to assemble the transition zone thus indicating that the anchoring process parallels the structural differentiation of the transition zone. This feature offers an opportunity to dissect spatio-temporally the mechanisms involved in the Basal Body anchoring process and transition zone formation.
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the conserved centrosomal protein for20 is required for assembly of the transition zone and Basal Body docking at the cell surface
Journal of Cell Science, 2012Co-Authors: Nicole Garreau De Loubresse, Michel Lemullois, A Aubussonfleury, Chloe Laligne, Jean CohenAbstract:Summary Within the FOP family of centrosomal proteins, the conserved FOR20 protein has been implicated in the control of primary cilium assembly in human cells. To ascertain its role in ciliogenesis, we have investigated the function of its ortholog, PtFOR20p, in the multiciliated unicellular organism Paramecium . Using combined functional and cytological analyses, we found that PtFOR20p specifically localises at Basal bodies and is required to build the transition zone, a prerequisite to their maturation and docking at the cell surface and hence to ciliogenesis. We also found that PtCen2p (one of the two Basal Body specific centrins, an ortholog of HsCen2) is required to recruit PtFOR20p at the developing Basal Body and to control its length. By contrast, the other Basal-Body-specific centrin PtCen3p is not needed for assembly of the transition zone, but is required downstream, for Basal Body docking. Comparison of the structural defects induced by depletion of PtFOR20p, PtCen2p or PtCen3p, respectively, illustrates the dual role of the transition zone in the biogenesis of the Basal Body and in cilium assembly. The multiple potential roles of the transition zone during Basal Body biogenesis and the evolutionary conserved function of the FOP proteins in microtubule membrane interactions are discussed.
Zakia Abdelhamed - One of the best experts on this subject based on the ideXlab platform.
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The Meckel-Gruber Syndrome protein TMEM67 (meckelin) regulates Basal Body planar polarization and non-canonical Wnt signalling via Wnt5a and ROR2
Cilia, 2015Co-Authors: Zakia Abdelhamed, Subaashini Natarajan, C. F. Inglehearn, Carmel Toomes, Colin A. JohnsonAbstract:Results: Tmem67 mutant phenotypes include pulmonary hypoplasia, ventricular septal defects, shortening of the Body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and Basal Body/ kinocilium positioning defects. The Basal Body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant Basal Body migration. TMEM67 (meckelin) is essential for phosphorylation of the noncanonical Wnt receptor ROR2 (receptor tyrosine kinaselike orphan receptor 2) upon Wnt5a stimulation. ROR2 interacts with the intracellular C-terminal domain of TMEM67 and co-localizes with TMEM67 at the ciliary transition zone. The N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Tmem67 mutant embryonic lungs in ex vivo culture failed to respond to Wnt5a stimulation of epithelial morphogenesis. However, stimulating the non-canonical Wnt pathway downstream of the receptor by activating RhoA resulted in an elicited response and the rescue of lung hypoplasia phenotypes.
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the meckel gruber syndrome protein tmem67 controls Basal Body positioning and epithelial branching morphogenesis in mice via the non canonical wnt pathway
Disease Models & Mechanisms, 2015Co-Authors: Zakia Abdelhamed, Subaashini Natarajan, C. F. Inglehearn, Carmel Toomes, Gabrielle Wheway, Colin A. JohnsonAbstract:Ciliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the Body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and Basal Body/kinocilium positioning defects. The Basal Body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant Basal Body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions.
