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Andrew P Jarman - One of the best experts on this subject based on the ideXlab platform.

  • Survey of the ciliary motility machinery of Drosophila sperm and ciliated mechanosensory neurons reveals unexpected cell-type specific variations: a model for Motile ciliopathies
    Frontiers in Genetics, 2019
    Co-Authors: Petra I. Zur Lage, Fay G. Newton, Andrew P Jarman
    Abstract:

    The Motile Cilium/flagellum is an ancient eukaryotic organelle. The molecular machinery of ciliary motility comprises a variety of Cilium-specific dynein motor complexes along with other complexes that regulate their activity. Assembling the motors requires the function of dedicated ‘assembly factors’ and transport processes. In humans, mutation of any one of at least 40 different genes encoding components of the motility apparatus causes Primary Ciliary Dyskinesia (PCD), a disease of defective ciliary motility. Recently, Drosophila has emerged as a model for Motile cilia biology and Motile ciliopathies. This is somewhat surprising as most Drosophila cells lack cilia, and Motile cilia are confined to just two specialised cell types: the sperm flagellum with a 9+2 axoneme and the ciliated dendrite of auditory/proprioceptive (chordotonal, Ch) neurons with a 9+0 axoneme. To determine the utility of Drosophila as a model for Motile cilia, we survey the Drosophila genome for ciliary motility gene homologues, and assess their expression and function. We find that the molecules of Cilium motility are well conserved in Drosophila. Most are readily characterised by their restricted cell-type specific expression patterns and phenotypes. There are also striking differences between the two Motile ciliated cell types. Notably, sperm and Ch neuron cilia express and require entirely different outer dynein arm variants – the first time this has been clearly established in any organism. These differences might reflect the specialised functions for motility in the two Cilium types. Moreover, the Ch neuron cilia lack the critical two-headed inner arm dynein (I1/f) but surprisingly retain key regulatory proteins previously associated with it. This may have implications for other Motile 9+0 cilia, including vertebrate embryonic nodal cilia required for left-right axis asymmetry. We discuss the possibility that cell-type specificity in ciliary motility machinery might occur in humans, and therefore underlie some of the phenotypic variation observed in PCD caused by different gene mutations. Our work lays the foundation for the increasing use of Drosophila as an excellent model for new Motile ciliary gene discovery and validation, for understanding Motile Cilium function and assembly, as well as understanding the nature of genetic defects underlying human Motile ciliopathies.

  • Table_1_Survey of the Ciliary Motility Machinery of Drosophila Sperm and Ciliated Mechanosensory Neurons Reveals Unexpected Cell-Type Specific Variations: A Model for Motile Ciliopathies.XLSX
    2019
    Co-Authors: Petra Zur Lage, Fay G. Newton, Andrew P Jarman
    Abstract:

    The Motile Cilium/flagellum is an ancient eukaryotic organelle. The molecular machinery of ciliary motility comprises a variety of Cilium-specific dynein motor complexes along with other complexes that regulate their activity. Assembling the motors requires the function of dedicated “assembly factors” and transport processes. In humans, mutation of any one of at least 40 different genes encoding components of the motility apparatus causes Primary Ciliary Dyskinesia (PCD), a disease of defective ciliary motility. Recently, Drosophila has emerged as a model for Motile cilia biology and Motile ciliopathies. This is somewhat surprising as most Drosophila cells lack cilia, and Motile cilia are confined to just two specialized cell types: the sperm flagellum with a 9+2 axoneme and the ciliated dendrite of auditory/proprioceptive (chordotonal, Ch) neurons with a 9+0 axoneme. To determine the utility of Drosophila as a model for Motile cilia, we survey the Drosophila genome for ciliary motility gene homologs, and assess their expression and function. We find that the molecules of Cilium motility are well conserved in Drosophila. Most are readily characterized by their restricted cell-type specific expression patterns and phenotypes. There are also striking differences between the two Motile ciliated cell types. Notably, sperm and Ch neuron cilia express and require entirely different outer dynein arm variants—the first time this has been clearly established in any organism. These differences might reflect the specialized functions for motility in the two Cilium types. Moreover, the Ch neuron cilia lack the critical two-headed inner arm dynein (I1/f) but surprisingly retain key regulatory proteins previously associated with it. This may have implications for other Motile 9+0 cilia, including vertebrate embryonic nodal cilia required for left-right axis asymmetry. We discuss the possibility that cell-type specificity in ciliary motility machinery might occur in humans, and therefore underlie some of the phenotypic variation observed in PCD caused by different gene mutations. Our work lays the foundation for the increasing use of Drosophila as an excellent model for new Motile ciliary gene discovery and validation, for understanding Motile Cilium function and assembly, as well as understanding the nature of genetic defects underlying human Motile ciliopathies.

  • Survey of the Ciliary Motility Machinery of Drosophila Sperm and Ciliated Mechanosensory Neurons Reveals Unexpected Cell-Type Specific Variations: A Model for Motile Ciliopathies
    Frontiers Media S.A., 2019
    Co-Authors: Petra Zur Lage, Fay G. Newton, Andrew P Jarman
    Abstract:

    The Motile Cilium/flagellum is an ancient eukaryotic organelle. The molecular machinery of ciliary motility comprises a variety of Cilium-specific dynein motor complexes along with other complexes that regulate their activity. Assembling the motors requires the function of dedicated “assembly factors” and transport processes. In humans, mutation of any one of at least 40 different genes encoding components of the motility apparatus causes Primary Ciliary Dyskinesia (PCD), a disease of defective ciliary motility. Recently, Drosophila has emerged as a model for Motile cilia biology and Motile ciliopathies. This is somewhat surprising as most Drosophila cells lack cilia, and Motile cilia are confined to just two specialized cell types: the sperm flagellum with a 9+2 axoneme and the ciliated dendrite of auditory/proprioceptive (chordotonal, Ch) neurons with a 9+0 axoneme. To determine the utility of Drosophila as a model for Motile cilia, we survey the Drosophila genome for ciliary motility gene homologs, and assess their expression and function. We find that the molecules of Cilium motility are well conserved in Drosophila. Most are readily characterized by their restricted cell-type specific expression patterns and phenotypes. There are also striking differences between the two Motile ciliated cell types. Notably, sperm and Ch neuron cilia express and require entirely different outer dynein arm variants—the first time this has been clearly established in any organism. These differences might reflect the specialized functions for motility in the two Cilium types. Moreover, the Ch neuron cilia lack the critical two-headed inner arm dynein (I1/f) but surprisingly retain key regulatory proteins previously associated with it. This may have implications for other Motile 9+0 cilia, including vertebrate embryonic nodal cilia required for left-right axis asymmetry. We discuss the possibility that cell-type specificity in ciliary motility machinery might occur in humans, and therefore underlie some of the phenotypic variation observed in PCD caused by different gene mutations. Our work lays the foundation for the increasing use of Drosophila as an excellent model for new Motile ciliary gene discovery and validation, for understanding Motile Cilium function and assembly, as well as understanding the nature of genetic defects underlying human Motile ciliopathies

  • the regulation of mechanosensory Motile Cilium formation
    Cilia, 2015
    Co-Authors: Andrew P Jarman, Zur P Lage, Girish R Mali, Pleasantine Mill
    Abstract:

    In contrast to the progress in understanding ciliogenesis and Cilium function, we know less about the pathways for generating ciliary diversity. Drosophila has a variety of sensory neurons with ciliary dendrites that are structurally and functionally specialised for receiving different sensory modalities. For instance, chordotonal (Ch) neurons have mechanosensory ciliary dendrites and are required for proprioception and hearing. Time-course gene expression profiling of differentiating Ch neurons allowed us to characterise the roles of two transcription factors for ciliogenic gene regulation: the well-known cilia gene regulator, Rfx, and a factor of the Forkhead family (Fd3F), which appears to be a diverged homologue of FOXJ1. Fd3F and Rfx cooperate to regulate a cohort of genes required for ciliary motility - in Drosophila this is a specialisation unique to Ch neuron cilia and is essential for the hearing mechanism. Analysing the target genes of Fd3F has led to the implication of new factors in the assembly of axonemal dynein complexes. Two of these are also mutated in human primary ciliary dyskinesia. Further analysis of these genes in Drosophila and mouse suggests that ZMYND10 may be linked to an emerging chaperone pathway, while HEATR2 appears to have a distinct function related to transport.

  • the regulation of mechanosensory Motile Cilium formation
    Cilia, 2015
    Co-Authors: Andrew P Jarman, Zur P Lage, Girish R Mali, Pleasantine Mill
    Abstract:

    In contrast to the progress in understanding ciliogenesis and Cilium function, we know less about the pathways for generating ciliary diversity. Drosophila has a variety of sensory neurons with ciliary dendrites that are structurally and functionally specialised for receiving different sensory modalities. For instance, chordotonal (Ch) neurons have mechanosensory ciliary dendrites and are required for proprioception and hearing. Time-course gene expression profiling of differentiating Ch neurons allowed us to characterise the roles of two transcription factors for ciliogenic gene regulation: the well-known cilia gene regulator, Rfx, and a factor of the Forkhead family (Fd3F), which appears to be a diverged homologue of FOXJ1. Fd3F and Rfx cooperate to regulate a cohort of genes required for ciliary motility - in Drosophila this is a specialisation unique to Ch neuron cilia and is essential for the hearing mechanism. Analysing the target genes of Fd3F has led to the implication of new factors in the assembly of axonemal dynein complexes. Two of these are also mutated in human primary ciliary dyskinesia. Further analysis of these genes in Drosophila and mouse suggests that ZMYND10 may be linked to an emerging chaperone pathway, while HEATR2 appears to have a distinct function related to transport.

Pleasantine Mill - One of the best experts on this subject based on the ideXlab platform.

  • the regulation of mechanosensory Motile Cilium formation
    Cilia, 2015
    Co-Authors: Andrew P Jarman, Zur P Lage, Girish R Mali, Pleasantine Mill
    Abstract:

    In contrast to the progress in understanding ciliogenesis and Cilium function, we know less about the pathways for generating ciliary diversity. Drosophila has a variety of sensory neurons with ciliary dendrites that are structurally and functionally specialised for receiving different sensory modalities. For instance, chordotonal (Ch) neurons have mechanosensory ciliary dendrites and are required for proprioception and hearing. Time-course gene expression profiling of differentiating Ch neurons allowed us to characterise the roles of two transcription factors for ciliogenic gene regulation: the well-known cilia gene regulator, Rfx, and a factor of the Forkhead family (Fd3F), which appears to be a diverged homologue of FOXJ1. Fd3F and Rfx cooperate to regulate a cohort of genes required for ciliary motility - in Drosophila this is a specialisation unique to Ch neuron cilia and is essential for the hearing mechanism. Analysing the target genes of Fd3F has led to the implication of new factors in the assembly of axonemal dynein complexes. Two of these are also mutated in human primary ciliary dyskinesia. Further analysis of these genes in Drosophila and mouse suggests that ZMYND10 may be linked to an emerging chaperone pathway, while HEATR2 appears to have a distinct function related to transport.

  • the regulation of mechanosensory Motile Cilium formation
    Cilia, 2015
    Co-Authors: Andrew P Jarman, Zur P Lage, Girish R Mali, Pleasantine Mill
    Abstract:

    In contrast to the progress in understanding ciliogenesis and Cilium function, we know less about the pathways for generating ciliary diversity. Drosophila has a variety of sensory neurons with ciliary dendrites that are structurally and functionally specialised for receiving different sensory modalities. For instance, chordotonal (Ch) neurons have mechanosensory ciliary dendrites and are required for proprioception and hearing. Time-course gene expression profiling of differentiating Ch neurons allowed us to characterise the roles of two transcription factors for ciliogenic gene regulation: the well-known cilia gene regulator, Rfx, and a factor of the Forkhead family (Fd3F), which appears to be a diverged homologue of FOXJ1. Fd3F and Rfx cooperate to regulate a cohort of genes required for ciliary motility - in Drosophila this is a specialisation unique to Ch neuron cilia and is essential for the hearing mechanism. Analysing the target genes of Fd3F has led to the implication of new factors in the assembly of axonemal dynein complexes. Two of these are also mutated in human primary ciliary dyskinesia. Further analysis of these genes in Drosophila and mouse suggests that ZMYND10 may be linked to an emerging chaperone pathway, while HEATR2 appears to have a distinct function related to transport.

Jeffrey D Axelrod - One of the best experts on this subject based on the ideXlab platform.

  • Planar Cell Polarity Enables Posterior Localization of Nodal Cilia and Left-Right Axis Determination during Mouse and Xenopus Embryogenesis
    PLOS ONE, 2010
    Co-Authors: Dragana Antic, Jennifer L. Stubbs, Chris Kintner, Kaye Suyama, Matthew P Scott, Jeffrey D Axelrod
    Abstract:

    Left-right asymmetry in vertebrates is initiated in an early embryonic structure called the ventral node in human and mouse, and the gastrocoel roof plate (GRP) in the frog. Within these structures, each epithelial cell bears a single Motile Cilium, and the concerted beating of these cilia produces a leftward fluid flow that is required to initiate left-right asymmetric gene expression. The leftward fluid flow is thought to result from the posterior tilt of the cilia, which protrude from near the posterior portion of each cell's apical surface. The cells, therefore, display a morphological planar polarization. Planar cell polarity (PCP) is manifested as the coordinated, polarized orientation of cells within epithelial sheets, or as directional cell migration and intercalation during convergent extension. A set of evolutionarily conserved proteins regulates PCP. Here, we provide evidence that vertebrate PCP proteins regulate planar polarity in the mouse ventral node and in the Xenopus gastrocoel roof plate. Asymmetric anterior localization of VANGL1 and PRICKLE2 (PK2) in mouse ventral node cells indicates that these cells are planar polarized by a conserved molecular mechanism. A weakly penetrant Vangl1 mutant phenotype suggests that compromised Vangl1 function may be associated with left-right laterality defects. Stronger functional evidence comes from the Xenopus GRP, where we show that perturbation of VANGL2 protein function disrupts the posterior localization of Motile cilia that is required for leftward fluid flow, and causes aberrant expression of the left side-specific gene Nodal. The observation of anterior-posterior PCP in the mouse and in Xenopus embryonic organizers reflects a strong evolutionary conservation of this mechanism that is important for body plan determination.

Dragana Antic - One of the best experts on this subject based on the ideXlab platform.

  • Planar Cell Polarity Enables Posterior Localization of Nodal Cilia and Left-Right Axis Determination during Mouse
    2013
    Co-Authors: Xenopus Embryogenesis, Jennifer L. Stubbs, Chris Kintner, Dragana Antic, Kaye Suyama, Matthew P Scott, Jeffrey D
    Abstract:

    Left-right asymmetry in vertebrates is initiated in an early embryonic structure called the ventral node in human and mouse, and the gastrocoel roof plate (GRP) in the frog. Within these structures, each epithelial cell bears a single Motile Cilium, and the concerted beating of these cilia produces a leftward fluid flow that is required to initiate left-right asymmetric gene expression. The leftward fluid flow is thought to result from the posterior tilt of the cilia, which protrude from near the posterior portion of each cell’s apical surface. The cells, therefore, display a morphological planar polarization. Planar cell polarity (PCP) is manifested as the coordinated, polarized orientation of cells within epithelial sheets, or as directional cell migration and intercalation during convergent extension. A set of evolutionarily conserved proteins regulates PCP. Here, we provide evidence that vertebrate PCP proteins regulate planar polarity in the mouse ventral node and in the Xenopus gastrocoel roof plate. Asymmetric anterior localization of VANGL1 and PRICKLE2 (PK2) in mouse ventral node cells indicates that these cells are planar polarized by a conserved molecular mechanism. A weakly penetrant Vangl1 mutant phenotype suggests that compromised Vangl1 function may be associated with left-right laterality defects. Stronger functional evidence comes from the Xenopus GRP, where we show that perturbation of VANGL2 protein function disrupts the posterior localization of Motile cilia that is required for leftward fluid flow, and causes aberrant expression of the left side-specific gene Nodal. The observation of anterior-posterior PCP in the mouse and in Xenopus embryonic organizers reflects a stron

  • Planar Cell Polarity Enables Posterior Localization of Nodal Cilia and Left-Right Axis Determination during Mouse and Xenopus Embryogenesis
    PLOS ONE, 2010
    Co-Authors: Dragana Antic, Jennifer L. Stubbs, Chris Kintner, Kaye Suyama, Matthew P Scott, Jeffrey D Axelrod
    Abstract:

    Left-right asymmetry in vertebrates is initiated in an early embryonic structure called the ventral node in human and mouse, and the gastrocoel roof plate (GRP) in the frog. Within these structures, each epithelial cell bears a single Motile Cilium, and the concerted beating of these cilia produces a leftward fluid flow that is required to initiate left-right asymmetric gene expression. The leftward fluid flow is thought to result from the posterior tilt of the cilia, which protrude from near the posterior portion of each cell's apical surface. The cells, therefore, display a morphological planar polarization. Planar cell polarity (PCP) is manifested as the coordinated, polarized orientation of cells within epithelial sheets, or as directional cell migration and intercalation during convergent extension. A set of evolutionarily conserved proteins regulates PCP. Here, we provide evidence that vertebrate PCP proteins regulate planar polarity in the mouse ventral node and in the Xenopus gastrocoel roof plate. Asymmetric anterior localization of VANGL1 and PRICKLE2 (PK2) in mouse ventral node cells indicates that these cells are planar polarized by a conserved molecular mechanism. A weakly penetrant Vangl1 mutant phenotype suggests that compromised Vangl1 function may be associated with left-right laterality defects. Stronger functional evidence comes from the Xenopus GRP, where we show that perturbation of VANGL2 protein function disrupts the posterior localization of Motile cilia that is required for leftward fluid flow, and causes aberrant expression of the left side-specific gene Nodal. The observation of anterior-posterior PCP in the mouse and in Xenopus embryonic organizers reflects a strong evolutionary conservation of this mechanism that is important for body plan determination.

Evelyn Houliston - One of the best experts on this subject based on the ideXlab platform.

  • A conserved function for Strabismus in establishing planar cell polarity in the ciliated ectoderm during cnidarian larval development
    Development, 2012
    Co-Authors: Tsuyoshi Momose, Yulia Kraus, Evelyn Houliston
    Abstract:

    Functional and morphological planar cell polarity (PCP) oriented along the oral-aboral body axis is clearly evident in the ectoderm of torpedo-shaped planula larvae of hydrozoan cnidarians such as Clytia hemisphaerica. Ectodermal epithelial cells bear a single Motile Cilium the beating of which is coordinated between cells, causing directional swimming towards the blunt, aboral pole. We have characterised PCP during Clytia larval development and addressed its molecular basis. PCP is first detectable in ectodermal cells during gastrulation as coordinated basal body positioning, the ciliary root becoming consistently positioned on the oral side of the apical surface of the cell. At later stages, more pronounced structural polarity develops around the base of each Cilium in relation to the cilia beating direction, including a characteristic asymmetric cortical actin organisation. Morpholino antisense oligonucleotide and mRNA injection studies showed that PCP development requires the Clytia orthologues of the core Fz-PCP pathway components Strabismus (CheStbm), Frizzled (CheFz1) and Dishevelled (CheDsh). Morpholinos targeting any of these components prevented ectodermal PCP, disrupted ciliogenesis and inhibited embryo elongation during gastrulation, which involves cell intercalation. We show that YFP-tagged CheStbm adopts a polarised intracellular distribution, localising preferentially to the aboral boundary of each cell, as has been demonstrated in Drosophila and some vertebrate PCP studies. Our findings in a cnidarian strongly suggest that the Fz-PCP pathway is a highly conserved and evolutionary ancient metazoan feature that is probably widely responsible for oriented swimming and/or feeding in relation to body axis in the many ciliated larval types found throughout the animal kingdom.