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The Journal of Pediatrics Mar 2021Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary... (Review)
Review
Ciliopathies are a collection of disorders related to cilia dysfunction. Cilia are specialized organelles that project from the surface of most cells. Motile and primary (sensory) cilia are essential structures and have wide ranging functions. Our understanding of the genetics, pathophysiology, and clinical manifestations of motile ciliopathies, including primary ciliary dyskinesia (PCD), has rapidly advanced since the disease was linked to ciliary ultrastructural defects nearly five decades ago. We will provide an overview of different types of cilia, their role in child health and disease, focusing on motile ciliopathies, and describe recent advances that have led to improved diagnostics and may yield therapeutic targets to restore ciliary structure and function.
Topics: Cilia; Ciliary Motility Disorders; Humans
PubMed: 33242470
DOI: 10.1016/j.jpeds.2020.11.040 -
Nature Reviews. Molecular Cell Biology Sep 2017Motile and non-motile (primary) cilia are nearly ubiquitous cellular organelles. The dysfunction of cilia causes diseases known as ciliopathies. The number of reported... (Review)
Review
Motile and non-motile (primary) cilia are nearly ubiquitous cellular organelles. The dysfunction of cilia causes diseases known as ciliopathies. The number of reported ciliopathies (currently 35) is increasing, as is the number of established (187) and candidate (241) ciliopathy-associated genes. The characterization of ciliopathy-associated proteins and phenotypes has improved our knowledge of ciliary functions. In particular, investigating ciliopathies has helped us to understand the molecular mechanisms by which the cilium-associated basal body functions in early ciliogenesis, as well as how the transition zone functions in ciliary gating, and how intraflagellar transport enables cargo trafficking and signalling. Both basic biological and clinical studies are uncovering novel ciliopathies and the ciliary proteins involved. The assignment of these proteins to different ciliary structures, processes and ciliopathy subclasses (first order and second order) provides insights into how this versatile organelle is built, compartmentalized and functions in diverse ways that are essential for human health.
Topics: Animals; Basal Bodies; Cilia; Ciliopathies; Humans; Microtubule-Associated Proteins; Signal Transduction
PubMed: 28698599
DOI: 10.1038/nrm.2017.60 -
Journal of Pediatric Genetics Jun 2014Nephronophthisis (NPHP) is a childhood cystic kidney disease, which almost invariably leads to end-stage renal disease in those affected. Recognition and diagnosis...
Nephronophthisis (NPHP) is a childhood cystic kidney disease, which almost invariably leads to end-stage renal disease in those affected. Recognition and diagnosis requires clinical suspicion, biochemical evaluation, renal imaging and historically, renal biopsy. Modern molecular genetics now allows a diagnosis to be made in a significant proportion of cases. Mutations in NPHP1 account for 20% of cases, but the disease is genetically heterogeneous with at least 20 different genes associated with NPHP. Recent developments in the fields of genetics and proteomics have led to increased understanding of the underlying pathogenetic defects. Almost all NPHP genes encode proteins, which localize to the primary cilia, basal body and centrosome. NPHP is a therefore considered to be a ciliopathy, and can be part of a broad spectrum of clinical disease that includes extra-renal manifestations including retinal degeneration, cerebellar ataxia, liver fibrosis and situs inversus. In this review, we discuss the historical descriptions of NPHP in the context of more recent developments in our understanding of this disease.
PubMed: 27625867
DOI: 10.3233/PGE-14086 -
Cilia 2015Tetrahymena thermophila is a ciliate with hundreds of cilia primarily used for cellular motility. These cells propel themselves by generating hydrodynamic forces through... (Review)
Review
Tetrahymena thermophila is a ciliate with hundreds of cilia primarily used for cellular motility. These cells propel themselves by generating hydrodynamic forces through coordinated ciliary beating. The coordination of cilia is ensured by the polarized organization of basal bodies (BBs), which exhibit remarkable structural and molecular conservation with BBs in other eukaryotes. During each cell cycle, massive BB assembly occurs and guarantees that future Tetrahymena cells gain a full complement of BBs and their associated cilia. BB duplication occurs next to existing BBs, and the predictable patterning of new BBs is facilitated by asymmetric BB accessory structures that are integrated with a membrane-associated cytoskeletal network. The large number of BBs combined with robust molecular genetics merits Tetrahymena as a unique model system to elucidate the fundamental events of BB assembly and organization.
PubMed: 26793300
DOI: 10.1186/s13630-016-0022-8 -
Cilia 2016In human cells, the basal body (BB) core comprises a ninefold microtubule-triplet cylindrical structure. Distal and subdistal appendages are located at the distal end of... (Review)
Review
In human cells, the basal body (BB) core comprises a ninefold microtubule-triplet cylindrical structure. Distal and subdistal appendages are located at the distal end of BB, where they play indispensable roles in cilium formation and function. Most cells that arrest in the G0 stage of the cell cycle initiate BB docking at the plasma membrane followed by BB-mediated growth of a solitary primary cilium, a structure required for sensing the extracellular environment and cell signaling. In addition to the primary cilium, motile cilia are present in specialized cells, such as sperm and airway epithelium. Mutations that affect BB function result in cilia dysfunction. This can generate syndromic disorders, collectively called ciliopathies, for which there are no effective treatments. In this review, we focus on the features and functions of BBs and centrosomes in Homo sapiens.
PubMed: 26981235
DOI: 10.1186/s13630-016-0030-8 -
Cilia 2015Xenopus has been one of the earliest and most important vertebrate model organisms for investigating the role and structure of basal bodies. Early transmission electron... (Review)
Review
Xenopus has been one of the earliest and most important vertebrate model organisms for investigating the role and structure of basal bodies. Early transmission electron microscopy studies in Xenopus revealed the fine structures of Xenopus basal bodies and their accessory structures. Subsequent investigations using multiciliated cells in the Xenopus epidermis have further revealed many important features regarding the transcriptional regulation of basal body amplification as well as the regulation of basal body/cilia polarity. Future basal body research using Xenopus is expected to focus on the application of modern genome editing techniques (CRISPR/TALEN) to characterize the components of basal body proteins and their molecular functions.
PubMed: 26848388
DOI: 10.1186/s13630-016-0024-6 -
Developmental Cell Apr 2019Several recent studies have revealed that nuclei and cilia share molecular components implicated in DNA damage response, splicing, gene expression, and... (Review)
Review
Several recent studies have revealed that nuclei and cilia share molecular components implicated in DNA damage response, splicing, gene expression, and sub-compartmentalization of the cell. We review evidence that exchange of components between the nucleus and cilia is facilitated by the centrosome, which contributes both to the mitotic apparatus of the nucleus and to the cilia structure. Moreover, the centrosome and the pericentriolar material form condensates that share components with stress granules and P-bodies, membrane-less organelles enriched in RNA and RNA-processing proteins. These features may largely explain the origin of similar molecular mechanisms in nuclei and cilia.
Topics: Animals; Cell Nucleus; Centrosome; Cilia; DNA Damage; Humans; Mitosis; Nuclear Pore; RNA Splicing; Spindle Apparatus
PubMed: 31014478
DOI: 10.1016/j.devcel.2019.03.009 -
Current Opinion in Cell Biology Aug 2022Multiciliated cells (MCC) are evolutionary conserved, highly specialized cell types that contain dozens to hundreds of motile cilia that they use to propel fluid... (Review)
Review
Multiciliated cells (MCC) are evolutionary conserved, highly specialized cell types that contain dozens to hundreds of motile cilia that they use to propel fluid directionally. To template these cilia, each MCC produces between 30 and 500 basal bodies via a process termed centriole amplification. Much progress has been made in recent years in understanding the pathways involved in MCC fate determination, differentiation, and ciliogenesis. Recent studies using mammalian cell culture systems, mice, Xenopus, and other model organisms have started to uncover the mechanisms involved in centriole and cilia biogenesis. Yet, how MCC progenitor cells regulate the precise number of centrioles and cilia during their differentiation remains largely unknown. In this review, we will examine recent findings that address this fundamental question.
Topics: Animals; Cell Differentiation; Centrioles; Cilia; Mammals; Mice; Xenopus laevis
PubMed: 35716530
DOI: 10.1016/j.ceb.2022.102105