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Key Points There are two types of cilia, motile and non-motile primary, which have different roles in human physiology, cell signalling and development. Ciliopathies are human disorders that arise from the dysfunction of motile and/or non-motile cilia. At least 35 different ciliopathies collectively affect nearly all organ systems, with prevalent phenotypes including polycystic kidney disease, retinal degeneration, obesity, skeletal malformations and brain anomalies. There are more than 180 known ciliopathy-associated proteins, and over 240 established ciliary proteins that represent candidate ciliopathy proteins. The basal body, transition zone and intraflagellar transport system represent hotspots for ciliopathies. Proteins that do not specifically localize to cilia may influence ciliary functions and cause ciliopathies, and ciliary proteins can have extraciliary functions. Many complementary approaches, coupled with the sequencing of the genomes of patients, are being carried out to uncover additional ciliary proteins and their associations with known or novel ciliopathies. Motile and non-motile primary cilia are nearly ubiquitous cellular organelles. Dysfunction of cilia is being found to cause increasing numbers of diseases that are known as ciliopathies. The characterization of ciliopathy-associated proteins and phenotypes is increasing our understanding of how cilia are formed and compartmentalized and how they function to maintain human health. 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.

Primary cilia project in a single copy from the surface of most vertebrate cell types; they detect and transmit extracellular cues to regulate diverse cellular processes during development and to maintain tissue homeostasis. The sensory capacity of primary cilia relies on the coordinated trafficking and temporal localization of specific receptors and associated signal transduction modules in the cilium. The canonical Hedgehog (HH) pathway, for example, is a bona fide ciliary signalling system that regulates cell fate and self-renewal in development and tissue homeostasis. Specific receptors and associated signal transduction proteins can also localize to primary cilia in a cell type-dependent manner; available evidence suggests that the ciliary constellation of these proteins can temporally change to allow the cell to adapt to specific developmental and homeostatic cues. Consistent with important roles for primary cilia in signalling, mutations that lead to their dysfunction underlie a pleiotropic group of diseases and syndromic disorders termed ciliopathies, which affect many different tissues and organs of the body. In this Review, we highlight central mechanisms by which primary cilia coordinate HH, G protein-coupled receptor, WNT, receptor tyrosine kinase and transforming growth factor-β (TGFβ)/bone morphogenetic protein (BMP) signalling and illustrate how defects in the balanced output of ciliary signalling events are coupled to developmental disorders and disease progression.This Review describes the main signalling pathways that are coordinated by primary cilia to control developmental processes, tissue plasticity and organ function and how defects in the output of ciliary signalling events are coupled to developmental disorders and disease progression.

Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. Here we examine the functional and structural consequences of SARS-CoV-2 infection in a reconstructed human bronchial epithelium model. SARS-CoV-2 replication causes a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remains limited. Rather, SARS-CoV-2 replication leads to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. Downregulation of the master regulator of ciliogenesis Foxj1 occurs prior to extensive cilia loss, implicating this transcription factor in the dedifferentiation of ciliated cells. Motile cilia function is compromised by SARS-CoV-2 infection, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramp up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrates the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma. SARS-CoV-2 infection damages the airways. Here the authors show that SARS-CoV-2 infection induces the rapid loss of airway motile cilia, resulting in altered cilia clearance function. Cilia loss is preceded by reduced expression of the ciliogenesis regulator Foxj1.

Key Points Centrosomes are not essential for cell division in most animal cells, although they contribute to the efficiency of mitotic spindle assembly. Centrosome loss is tolerated surprisingly well in fly cells, but it normally induces a p53-dependent block to proliferation or apoptosis in vertebrate cells. Centrosome dysfunction in humans may promote cancer by increasing levels of chromosomal instability and/or the metastatic potential of cancer cells, although strong genetic evidence for this link is lacking. Strong genetic evidence links centrosome dysfunction to microcephaly and primordial dwarfism in humans, although the reasons for this link are unclear. There have been dramatic recent advances in our molecular understanding of how centrioles and centrosomes assemble. In flies and in worms, the SPD2 and Polo or Polo-like kinase 1 (PLK1) proteins cooperate with Cnn (in flies) or SPD-5 (in worms), to drive the assembly of a scaffold structure around the mother centriole during mitosis that functions to recruit other proteins to the mitotic centrosome. Centrosomes are important microtubule organizers. As many proteins are concentrated at centrosomes, including cell cycle and signalling regulators, centrosomes are also likely to coordinate important cell decisions. Recent findings have shed light on the functions of centrosomes in animal cells and on the mechanisms of centrosome assembly and maturation during mitosis. It has become clear that the role of centrosomes extends well beyond that of important microtubule organizers. There is increasing evidence that they also function as coordination centres in eukaryotic cells, at which specific cytoplasmic proteins interact at high concentrations and important cell decisions are made. Accordingly, hundreds of proteins are concentrated at centrosomes, including cell cycle regulators, checkpoint proteins and signalling molecules. Nevertheless, several observations have raised the question of whether centrosomes are essential for many cell processes. Recent findings have shed light on the functions of centrosomes in animal cells and on the molecular mechanisms of centrosome assembly, in particular during mitosis. These advances should ultimately allow the in vitro reconstitution of functional centrosomes from their component proteins to unlock the secrets of these enigmatic organelles.

The primary cilium is a hair-like surface-exposed organelle of the eukaryotic cell that decodes a variety of signals — such as odorants, light and Hedgehog morphogens — by altering the local concentrations and activities of signalling proteins. Signalling within the cilium is conveyed through a diverse array of second messengers, including conventional signalling molecules (such as cAMP) and some unusual intermediates (such as sterols). Diffusion barriers at the ciliary base establish the unique composition of this signalling compartment, and cilia adapt their proteome to signalling demands through regulated protein trafficking. Much progress has been made on the molecular understanding of regulated ciliary trafficking, which encompasses not only exchanges between the cilium and the rest of the cell but also the shedding of signalling factors into extracellular vesicles.Cilia, and primary cilia in particular, are important signalling organelles with established roles in odorant, light and Hedgehog morphogen signal transduction. Cilia are enriched in signalling receptors and effectors and in specific lipids. Addressing how this unique composition is established and maintained is key to understanding cell signalling.

Key Points Planar cell polarity (PCP) is a polarity axis that organizes cells in the plane of the tissue. PCP is conserved in metazoans and is essential for proper development and tissue homeostasis. Asymmetric and mutually exclusive subcellular enrichment of key PCP proteins patterns cells in planar-polarized tissues. PCP proteins also coordinate planar polarity between cells and control polarized behaviours by modulating the cytoskeleton. PCP patterns develop gradually from an initially disordered state through dynamic trafficking and various feedback interactions that can influence protein localization and stability. PCP patterns seem to be globally oriented along a pre-defined axis in a given tissue. Notably, multiple mechanistic inputs may have differential influences on PCP patterning depending on developmental timing and tissue context, and may only partially overlap in different contexts. The morphogenetic events governed by PCP signalling are best understood in Drosophila melanogaster , in which the particular orientation of hairs and bristles on the fly body has served to unravel basic principles of PCP-dependent processes. Information obtained from this model has helped to better understand equivalent mechanisms in vertebrates, particularly in the context of the orientation of fluid flow mediated by multiciliated cells and cell rearrangements during convergent extension. Mutations in PCP genes have been implicated in diverse human pathologies, and the body of evidence supporting the involvement of PCP aberrations in human birth defects continues to grow rapidly. Planar cell polarity — the asymmetric distribution of proteins in the plane of a cell sheet — dictates the orientation of various subcellular structures and drives collective cell rearrangements. Better understanding of this conserved axis of polarity can shed light on the mechanisms of morphogenetic processes and explain the underlying causes of human birth defects. Planar cell polarity (PCP) is an essential feature of animal tissues, whereby distinct polarity is established within the plane of a cell sheet. Tissue-wide establishment of PCP is driven by multiple global cues, including gradients of gene expression, gradients of secreted WNT ligands and anisotropic tissue strain. These cues guide the dynamic, subcellular enrichment of PCP proteins, which can self-assemble into mutually exclusive complexes at opposite sides of a cell. Endocytosis, endosomal trafficking and degradation dynamics of PCP components further regulate planar tissue patterning. This polarization propagates throughout the whole tissue, providing a polarity axis that governs collective morphogenetic events such as the orientation of subcellular structures and cell rearrangements. Reflecting the necessity of polarized cellular behaviours for proper development and function of diverse organs, defects in PCP have been implicated in human pathologies, most notably in severe birth defects.

Cilia play essential roles in normal human development and health; cilia dysfunction results in diseases such as primary ciliary dyskinesia (PCD). Despite their importance, the native structure of human cilia is unknown, and structural defects in the cilia of patients are often undetectable or remain elusive because of heterogeneity. Here we develop an approach that enables visualization of human (patient) cilia at high-resolution using cryo-electron tomography of samples obtained noninvasively by nasal scrape biopsy. We present the native 3D structures of normal and PCD-causing RSPH1- mutant human respiratory cilia in unprecedented detail; this allows comparisons of cilia structure across evolutionarily distant species and reveals the previously unknown primary defect and the heterogeneous secondary defects in RSPH1 -mutant cilia. Our data provide evidence for structural and functional heterogeneity in radial spokes, suggest a mechanism for the milder RSPH1 PCD phenotype and demonstrate that cryo-electron tomography can be applied to human disease by directly imaging patient samples. Our current understanding of cilia biology and ciliary diseases is incomplete, in part because cilia are hard to visualize. Here, the authors use cryo-electron tomography to image the structure of human cilia with high resolution and uncover the elusive ciliary defects in Primary Ciliary Dyskinesia patients.

Motile cilia and flagella beat rhythmically on the surface of cells to power the flow of fluid and to enable spermatozoa and unicellular eukaryotes to swim. In humans, defective ciliary motility can lead to male infertility and a congenital disorder called primary ciliary dyskinesia (PCD), in which impaired clearance of mucus by the cilia causes chronic respiratory infections 1 . Ciliary movement is generated by the axoneme, a molecular machine consisting of microtubules, ATP-powered dynein motors and regulatory complexes 2 . The size and complexity of the axoneme has so far prevented the development of an atomic model, hindering efforts to understand how it functions. Here we capitalize on recent developments in artificial intelligence-enabled structure prediction and cryo-electron microscopy (cryo-EM) to determine the structure of the 96-nm modular repeats of axonemes from the flagella of the alga Chlamydomonas reinhardtii and human respiratory cilia. Our atomic models provide insights into the conservation and specialization of axonemes, the interconnectivity between dyneins and their regulators, and the mechanisms that maintain axonemal periodicity. Correlated conformational changes in mechanoregulatory complexes with their associated axonemal dynein motors provide a mechanism for the long-hypothesized mechanotransduction pathway to regulate ciliary motility. Structures of respiratory-cilia doublet microtubules from four individuals with PCD reveal how the loss of individual docking factors can selectively eradicate periodically repeating structures. Detailed atomic models of axonemes from algal flagella and human respiratory cilia, which are hair-like protrusions from cells that enable motility and clear mucus from human airways, could provide insights into how they function.

Key Points Cell biological studies have identified roles for dynein motors in many in vivo processes. These include transporting diverse intracellular cargo along microtubules, organizing microtubules within the cell division machinery and powering the beating of cilia and flagella. Unlike myosin and kinesin, which share an ancestry with G proteins, dynein evolved from the AAA+ superfamily of ring-shaped ATPases. In outline, the mechanochemical cycle of dynein is similar to that of myosin, but the underlying mechanism of its movement is quite different. Recent structural studies point towards a model in which nucleotide-driven flexing motions in the dynein AAA+ ring are coupled to the remodelling of a mechanical element called the linker domain. The ATPase and microtubule-binding domains of dynein are spatially separated by a coiled-coil stalk, which is thought to mediate allosteric communication via small sliding movements between its constituent α-helices. Single-molecule studies are starting to reveal how the paired motor domains in cytoplasmic dynein dimers move along microtubules, but the extent to which the motor domains communicate with each other and how much force they produce are controversial. Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes. A model for the mechanochemical cycle of dynein is emerging, in which nucleotide-driven flexing motions within the AAA+ ring of dynein alter the affinity of its microtubule-binding 'stalk' and reshape its mechanical element to generate movement. Fuelled by ATP hydrolysis, dyneins generate force and movement on microtubules in a wealth of biological processes, including ciliary beating, cell division and intracellular transport. The large mass and complexity of dynein motors have made elucidating their mechanisms a sizable task. Yet, through a combination of approaches, including X-ray crystallography, cryo-electron microscopy, single-molecule assays and biochemical experiments, important progress has been made towards understanding how these giant motor proteins work. From these studies, a model for the mechanochemical cycle of dynein is emerging, in which nucleotide-driven flexing motions within the AAA+ ring of dynein alter the affinity of its microtubule-binding stalk and reshape its mechanical element to generate movement.

The primary cilium is an antenna-like, immotile organelle present on most types of mammalian cells, which interprets extracellular signals that regulate growth and development. Although once considered a vestigial organelle, the primary cilium is now the focus of considerable interest. We now know that ciliary defects lead to a panoply of human diseases, termed ciliopathies, and the loss of this organelle may be an early signature event during oncogenic transformation. Ciliopathies include numerous seemingly unrelated developmental syndromes, with involvement of the retina, kidney, liver, pancreas, skeletal system and brain. Recent studies have begun to clarify the key mechanisms that link cilium assembly and disassembly to the cell cycle, and suggest new possibilities for therapeutic intervention. Sanchez and Dynlacht discuss recent insights into the mechanisms of primary cilia assembly and disassembly, and the relationships between ciliogenesis and cell cycle regulation as well as disease.