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The World Journal of Men's Health Jan 2020Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and... (Review)
Review
Microtubules are the prime component of the cytoskeleton along with microfilaments. Being vital for organelle transport and cellular divisions during spermatogenesis and sperm motility process, microtubules ascertain functional capacity of sperm. Also, microtubule based structures such as axoneme and manchette are crucial for sperm head and tail formation. This review (a) presents a concise, yet detailed structural overview of the microtubules, (b) analyses the role of microtubule structures in various male reproductive functions, and (c) presents the association of microtubular dysfunctions with male infertility. Considering the immense importance of microtubule structures in the formation and maintenance of physiological functions of sperm cells, this review serves as a scientific trigger in stimulating further male infertility research in this direction.
PubMed: 30350487
DOI: 10.5534/wjmh.180066 -
Proceedings of the National Academy of... Jul 2023Cilia build distinct subdomains with variable axonemal structures to perform diverse functions in cell motility and signaling. In sensory cilia across species, an...
Cilia build distinct subdomains with variable axonemal structures to perform diverse functions in cell motility and signaling. In sensory cilia across species, an axoneme differentiates longitudinally into a middle segment with nine microtubule (MT) doublets and a distal segment with nine MT singlets that extends from the A tubules of the doublets. Here, we study axoneme differentiation in by analyzing the flagellar inner junction protein FAP20 and PCRG1 that connect A and B tubules in . The nematode CFAP-20 is restricted to the middle segment with doublets, and its loss disconnects A and B tubules. However, PCRG-1 is absent from most sensory cilia, and its deletion does not disrupt cilia. Ectopic introduction of PCRG-1 into cilia generated abnormal MT doublets in the distal segment and reduced intraflagellar transport and animal sensation. Thus, the absence of an inner junction protein prevents B-tubule extension, which contributes to axoneme differentiation and ciliary function.
Topics: Animals; Axoneme; Cilia; Chlamydomonas; Caenorhabditis elegans; Biological Transport; Microtubules; Flagella
PubMed: 37463209
DOI: 10.1073/pnas.2303955120 -
Cell Oct 2019The axoneme of motile cilia is the largest macromolecular machine of eukaryotic cells. In humans, impaired axoneme function causes a range of ciliopathies. Axoneme...
The axoneme of motile cilia is the largest macromolecular machine of eukaryotic cells. In humans, impaired axoneme function causes a range of ciliopathies. Axoneme assembly, structure, and motility require a radially arranged set of doublet microtubules, each decorated in repeating patterns with non-tubulin components. We use single-particle cryo-electron microscopy to visualize and build an atomic model of the repeating structure of a native axonemal doublet microtubule, which reveals the identities, positions, repeat lengths, and interactions of 38 associated proteins, including 33 microtubule inner proteins (MIPs). The structure demonstrates how these proteins establish the unique architecture of doublet microtubules, maintain coherent periodicities along the axoneme, and stabilize the microtubules against the repeated mechanical stress induced by ciliary motility. Our work elucidates the architectural principles that underpin the assembly of this large, repetitive eukaryotic structure and provides a molecular basis for understanding the etiology of human ciliopathies.
Topics: Axoneme; Cell Movement; Cilia; Ciliopathies; Cryoelectron Microscopy; Humans; Microtubule Proteins; Microtubules; Stress, Mechanical
PubMed: 31668805
DOI: 10.1016/j.cell.2019.09.030 -
Cell Nov 2021Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned...
Dynein-decorated doublet microtubules (DMTs) are critical components of the oscillatory molecular machine of cilia, the axoneme, and have luminal surfaces patterned periodically by microtubule inner proteins (MIPs). Here we present an atomic model of the 48-nm repeat of a mammalian DMT, derived from a cryoelectron microscopy (cryo-EM) map of the complex isolated from bovine respiratory cilia. The structure uncovers principles of doublet microtubule organization and features specific to vertebrate cilia, including previously unknown MIPs, a luminal bundle of tektin filaments, and a pentameric dynein-docking complex. We identify a mechanism for bridging 48- to 24-nm periodicity across the microtubule wall and show that loss of the proteins involved causes defective ciliary motility and laterality abnormalities in zebrafish and mice. Our structure identifies candidate genes for diagnosis of ciliopathies and provides a framework to understand their functions in driving ciliary motility.
Topics: Amino Acid Sequence; Animals; Cattle; Cilia; Cryoelectron Microscopy; Dyneins; Embryo, Mammalian; Female; Male; Mammals; Mice, Inbred C57BL; Microtubule Proteins; Microtubules; Models, Molecular; Mutation; Proteins; Trachea; Zebrafish; Zebrafish Proteins; Mice
PubMed: 34715025
DOI: 10.1016/j.cell.2021.10.007 -
Advances in Parasitology 2020Giardia lamblia is a widespread parasitic protist with a complex MT cytoskeleton that is critical for motility, attachment, mitosis and cell division, and transitions... (Review)
Review
Giardia lamblia is a widespread parasitic protist with a complex MT cytoskeleton that is critical for motility, attachment, mitosis and cell division, and transitions between its two life cycle stages-the infectious cyst and flagellated trophozoite. Giardia trophozoites have both highly dynamic and highly stable MT organelles, including the ventral disc, eight flagella, the median body and the funis. The ventral disc, an elaborate MT organelle, is essential for the parasite's attachment to the intestinal villi to avoid peristalsis. Giardia's four flagellar pairs enable swimming motility and may also promote attachment. They are maintained at different equilibrium lengths and are distinguished by their long cytoplasmic regions and novel extra-axonemal structures. The functions of the median body and funis, MT organelles unique to Giardia, remain less understood. In addition to conserved MT-associated proteins, the genome is enriched in ankyrins, NEKs, and novel hypothetical proteins that also associate with the MT cytoskeleton. High-resolution ultrastructural imaging and a current inventory of more than 300 proteins associated with Giardia's MT cytoskeleton lay the groundwork for future mechanistic analyses of parasite attachment to the host, motility, cell division, and encystation/excystation. Giardia's unique MT organelles exemplify the capacity of MT polymers to generate intricate structures that are diverse in both form and function. Thus, beyond its relevance to pathogenesis, the study of Giardia's MT cytoskeleton informs basic cytoskeletal biology and cellular evolution. With the availability of new molecular genetic tools to disrupt gene function, we anticipate a new era of cytoskeletal discovery in Giardia.
Topics: Giardia; Microtubules; Organelles
PubMed: 32122531
DOI: 10.1016/bs.apar.2019.11.001 -
Annual Review of Biophysics May 2021Dyneins make up a family of AAA+ motors that move toward the minus end of microtubules. Cytoplasmic dynein is responsible for transporting intracellular cargos in... (Review)
Review
Dyneins make up a family of AAA+ motors that move toward the minus end of microtubules. Cytoplasmic dynein is responsible for transporting intracellular cargos in interphase cells and mediating spindle assembly and chromosome positioning during cell division. Other dynein isoforms transport cargos in cilia and power ciliary beating. Dyneins were the least studied of the cytoskeletal motors due to challenges in the reconstitution of active dynein complexes in vitro and the scarcity of high-resolution methods for in-depth structural and biophysical characterization of these motors. These challenges have been recently addressed, and there have been major advances in our understanding of the activation, mechanism, and regulation of dyneins. This review synthesizes the results of structural and biophysical studies for each class of dynein motors. We highlight several outstanding questions about the regulation of bidirectional transport along microtubules and the mechanisms that sustain self-coordinated oscillations within motile cilia.
Topics: Animals; Biological Transport; Cilia; Dyneins; Humans; Intracellular Space; Microtubules
PubMed: 33957056
DOI: 10.1146/annurev-biophys-111020-101511 -
International Journal of Molecular... Sep 2021Primary cilia are non-motile, cell cycle-associated organelles that can be found on most vertebrate cell types. Comprised of microtubule bundles organised into an... (Review)
Review
Primary cilia are non-motile, cell cycle-associated organelles that can be found on most vertebrate cell types. Comprised of microtubule bundles organised into an axoneme and anchored by a mature centriole or basal body, primary cilia are dynamic signalling platforms that are intimately involved in cellular responses to their extracellular milieu. Defects in ciliogenesis or dysfunction in cilia signalling underlie a host of developmental disorders collectively referred to as ciliopathies, reinforcing important roles for cilia in human health. Whilst primary cilia have long been recognised to be present in striated muscle, their role in muscle is not well understood. However, recent studies indicate important contributions, particularly in skeletal muscle, that have to date remained underappreciated. Here, we explore recent revelations that the sensory and signalling functions of cilia on muscle progenitors regulate cell cycle progression, trigger differentiation and maintain a commitment to myogenesis. Cilia disassembly is initiated during myoblast fusion. However, the remnants of primary cilia persist in multi-nucleated myotubes, and we discuss their potential role in late-stage differentiation and myofiber formation. Reciprocal interactions between cilia and the extracellular matrix (ECM) microenvironment described for other tissues may also inform on parallel interactions in skeletal muscle. We also discuss emerging evidence that cilia on fibroblasts/fibro-adipogenic progenitors and myofibroblasts may influence cell fate in both a cell autonomous and non-autonomous manner with critical consequences for skeletal muscle ageing and repair in response to injury and disease. This review addresses the enigmatic but emerging role of primary cilia in satellite cells in myoblasts and myofibers during myogenesis, as well as the wider tissue microenvironment required for skeletal muscle formation and homeostasis.
Topics: Animals; Axoneme; Cell Cycle; Cell Differentiation; Centrosome; Cilia; Cytoskeleton; Extracellular Matrix; Humans; Muscle Development; Muscle Fibers, Skeletal; Muscle, Skeletal; Myoblasts; Organelles; Signal Transduction
PubMed: 34502512
DOI: 10.3390/ijms22179605 -
Nature Communications Oct 2021TRIP6, a member of the ZYXIN-family of LIM domain proteins, is a focal adhesion component. Trip6 deletion in the mouse, reported here, reveals a function in the brain:...
TRIP6, a member of the ZYXIN-family of LIM domain proteins, is a focal adhesion component. Trip6 deletion in the mouse, reported here, reveals a function in the brain: ependymal and choroid plexus epithelial cells are carrying, unexpectedly, fewer and shorter cilia, are poorly differentiated, and the mice develop hydrocephalus. TRIP6 carries numerous protein interaction domains and its functions require homodimerization. Indeed, TRIP6 disruption in vitro (in a choroid plexus epithelial cell line), via RNAi or inhibition of its homodimerization, confirms its function in ciliogenesis. Using super-resolution microscopy, we demonstrate TRIP6 localization at the pericentriolar material and along the ciliary axoneme. The requirement for homodimerization which doubles its interaction sites, its punctate localization along the axoneme, and its co-localization with other cilia components suggest a scaffold/co-transporter function for TRIP6 in cilia. Thus, this work uncovers an essential role of a LIM-domain protein assembly factor in mammalian ciliogenesis.
Topics: Adaptor Proteins, Signal Transducing; Animals; Brain; Ependyma; Focal Adhesions; Gene Expression Regulation; LIM Domain Proteins; Mice; Mice, Knockout; RNA Interference; Transcription Factors; Transcriptome
PubMed: 34620853
DOI: 10.1038/s41467-021-26057-6 -
FEBS Letters Nov 2020Cilia and microvilli are membrane protrusions that extend from the surface of many different mammalian cell types. Motile cilia or flagella are only found on specialized... (Review)
Review
Cilia and microvilli are membrane protrusions that extend from the surface of many different mammalian cell types. Motile cilia or flagella are only found on specialized cells, where they control cell movement or the generation of fluid flow, whereas immotile primary cilia protrude from the surface of almost every mammalian cell to detect and transduce extracellular signals. Despite these differences, all cilia consist of a microtubule core called the axoneme. Microvilli instead contain bundled linear actin filaments and are mainly localized on epithelial cells, where they modulate the absorption of nutrients. Cilia and microvilli constitute subcellular compartments with distinctive lipid and protein repertoires and specialized functions. Here, we summarize the role of sphingolipids in defining the identity and controlling the function of cilia and microvilli in mammalian cells.
Topics: Animals; Cilia; Humans; Microvilli; Sphingolipids
PubMed: 32415987
DOI: 10.1002/1873-3468.13816 -
Frontiers in Physiology 2021In artery tree, endothelial function correlates with the distribution of shear stress, a dragging force generated by flowing blood. In laminar shear stress areas,... (Review)
Review
In artery tree, endothelial function correlates with the distribution of shear stress, a dragging force generated by flowing blood. In laminar shear stress areas, endothelial cells (ECs) are available to prevent atherosclerosis, however, ECs in disturbed shear stress sites are featured with proinflammation and atherogenesis. Basic studies in the shear stress field that focused on the mechanosensors of ECs have attracted the interest of researchers. Among all the known mechanosensors, the primary cilium is distinctive because it is enriched in disturbed shear stress regions and sparse in laminar shear stress areas. The primary cilium, a rod liked micro-organelle, can transmit extracellular mechanical and chemical stimuli into intracellular space. In the cardiovascular system, primary cilia are enriched in disturbed shear stress regions, where blood flow is slow and oscillatory, such as the atrium, downstream of the aortic valve, branches, bifurcations, and inner curves of the artery. However, in the atrioventricular canal and straight vessels, blood flow is laminar, and primary cilia can barely be detected. Primary cilia in the heart cavity prevent ECs from mesenchymal transition and calcification by suppressing transforming growth factor (TGF) signaling. Besides, primary cilia in the vascular endothelium protected ECs against disturbed shear stress-induced cellular damage by triggering Ca influx as well as nitric oxide (NO) release. Moreover, primary cilia inhibit the process of atherosclerosis. In the current review, we discussed ciliogenesis, ciliary structure, as well as ciliary distribution, function and the coordinate signal transduction with shear stress in the cardiovascular system.
PubMed: 33633590
DOI: 10.3389/fphys.2021.640774