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Structure of cilia in the mouse respiratory and olfactory epithelium. ( A – C ) Transmission electron micrographs of an adult mouse olfactory epithelium; ( A ) The respiratory epithelium contains multiple motile cilia on one cell; ( B ) Higher magnification of a cross section showing the (9 × 2 + 2) microtubule configuration of olfactory cilia; ( C ) Longitudinal section of an olfactory knob (OK) with extending olfactory cilia (OC); ( D ) Schematics of an olfactory sensory neuron (OSN) and its olfactory knob. OSNs are the receptor elements of the olfactory system. They are surrounded by supporting cells (SC) with a microvilli (MV) border on their apical surface and continually replaced by basal cells (BC) throughout life. OSNs are bipolar neurons with dendrites ending in an olfactory knob which has specialized sensory cilia responsible for olfaction. The mammalian olfactory cilium comprises the transition zone (TZ), the proximal segment (PS), and the distal segment (DS). The TZ (9 × 2 + 0 structure) is located at the base of the olfactory cilium between the basal body and the origin of the axoneme’s central pair of microtubules. The PS projects from the basal body in a (9 × 2 + 2) configuration. The DS represents the end of the cilium and contains characteristic arrays of singlet microtubules (from 9 × 1 to 2 × 1); ( E – H ) Higher magnification electron micrographs showing the different microtubule configurations of the DS ( E – G ) and PS (H) of an olfactory cilium. CS: centrosomes. BL: basal lamina. Scale bars: 500 nm ( A , C ), 200 nm ( B ), 100 nm ( E – H ). 

Structure of cilia in the mouse respiratory and olfactory epithelium. ( A – C ) Transmission electron micrographs of an adult mouse olfactory epithelium; ( A ) The respiratory epithelium contains multiple motile cilia on one cell; ( B ) Higher magnification of a cross section showing the (9 × 2 + 2) microtubule configuration of olfactory cilia; ( C ) Longitudinal section of an olfactory knob (OK) with extending olfactory cilia (OC); ( D ) Schematics of an olfactory sensory neuron (OSN) and its olfactory knob. OSNs are the receptor elements of the olfactory system. They are surrounded by supporting cells (SC) with a microvilli (MV) border on their apical surface and continually replaced by basal cells (BC) throughout life. OSNs are bipolar neurons with dendrites ending in an olfactory knob which has specialized sensory cilia responsible for olfaction. The mammalian olfactory cilium comprises the transition zone (TZ), the proximal segment (PS), and the distal segment (DS). The TZ (9 × 2 + 0 structure) is located at the base of the olfactory cilium between the basal body and the origin of the axoneme’s central pair of microtubules. The PS projects from the basal body in a (9 × 2 + 2) configuration. The DS represents the end of the cilium and contains characteristic arrays of singlet microtubules (from 9 × 1 to 2 × 1); ( E – H ) Higher magnification electron micrographs showing the different microtubule configurations of the DS ( E – G ) and PS (H) of an olfactory cilium. CS: centrosomes. BL: basal lamina. Scale bars: 500 nm ( A , C ), 200 nm ( B ), 100 nm ( E – H ). 

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Cilia and flagella are highly conserved and important microtubule-based organelles that project from the surface of eukaryotic cells and act as antennae to sense extracellular signals. Moreover, cilia have emerged as key players in numerous physiological, developmental, and sensory processes such as hearing, olfaction, and photoreception. Genetic d...

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... sensory neurons (OSN) are the receptor elements of the olfactory system. OSNs are bipolar neurons whose dendrites end in an olfactory knob, where their cilia are localized (Figure 3). OSNs are surrounded by supporting cells, which have a microvilli border on their apical surface ( Figure 3C,D). ...
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... are bipolar neurons whose dendrites end in an olfactory knob, where their cilia are localized (Figure 3). OSNs are surrounded by supporting cells, which have a microvilli border on their apical surface ( Figure 3C,D). In all vertebrates, olfactory receptor cells display cycles of birth, maturation and death. ...
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... contrast, the multiple cilia in the respiratory epithelium with a (9 × 2 + 2) microtubule backbone are motile and play a role in mucociliary clearance [3] (Figure 3A,B). The mammalian olfactory cilium is approximately 50-60 μm long-recent studies have shown the length of murine cilia to vary between 2.5 and 110 µm [45]-and can be divided into the transition zone (TZ), the proximal (PS) and the distal segment (DS) (Figure 3D-H). ...
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... contrast, the multiple cilia in the respiratory epithelium with a (9 × 2 + 2) microtubule backbone are motile and play a role in mucociliary clearance [3] (Figure 3A,B). The mammalian olfactory cilium is approximately 50-60 μm long-recent studies have shown the length of murine cilia to vary between 2.5 and 110 µm [45]-and can be divided into the transition zone (TZ), the proximal (PS) and the distal segment (DS) (Figure 3D-H). The TZ ("ciliary necklace") lies at the base of the olfactory cilium, where the lipid membrane sheath contacts the dendritic knob. ...
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... TZ ("ciliary necklace") lies at the base of the olfactory cilium, where the lipid membrane sheath contacts the dendritic knob. This domain is located between the basal body and the origin of the central pair of microtubules (9 × 2 + 0 structure, Figures 3D and 4D-F) of the axoneme [1]. Interestingly, ciliary transport proteins have been found to be localized at transitional fibers (which anchor the basal body to the membrane and are located under the transition zone), indicating that the TZ might serve as a cargo-docking site connecting the ciliary shaft to the protein complex at the base of the cilium [46,47]. ...
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... PS starts 2-3 µm away from the basal body in a (9 × 2 + 2) configuration and has a diameter of around 300 nm [48,49]. The thinner distal segment spans the upper part of the cilium, with the microtubule configuration going down from 9 × 1 to 4 × 1, usually ending with a pair of singlet microtubules ( Figure 3D-H). The DSes of olfactory cilia are oriented parallel to the epithelial surface. ...

Citations

... MWCNTs played a similar role to the cilia of bacteria ( Fig. 2a-1). There are two major classes of cilia: motile and non-motile cilia (Falk et al. 2015). In addition to motor functions, cilia also play a role in cellular communication and molecular transport. ...
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Printing technology for electronic devices has garnered considerable attention owing to its rapid and massive productivity under ambient conditions. In this study, a facile approach is proposed for manufacturing cellulose paper-based strain sensors with Ni/multi-walled carbon nanotube (MWCNT) composites using roll stamping technology. This process enables the fabrication of stable sensing structures owing to the formation of stable Ni core-enveloping structures in the MWCNT interlacing network. In particular, the rheological properties of the composites revealed shear thinning and thixotropic behavior, which resulted in fine printing of the sensing electrodes. Furthermore, the shape of the printed patterns, imparted by the pattern morphology, significantly influenced the strain-sensing performance. In particular, the Ni/MWCNT composite-based strain sensor exhibited a higher gauge factor of 13.9, with a high sensing recovery of 90.4% and stability over 23,500 bending cycles.
... Fundamental to the sensory apparatus are cilia and microvilli, cellular protrusions supported by microtubule or actin cores, respectively. Much recent research has focused on the importance of cilia in development, physiology, and disease (Anvarian et al., 2019;Falk et al., 2015;Horani & Ferkol, 2016). Here, we review the microvilli of sensory neurons, with a particular focus on similarities and differences in the structural components across cell types. ...
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Sensory neurons use specialized apical processes to perceive external stimuli and monitor internal body conditions. The apical apparatus can include cilia, microvilli, or both, and is adapted for the functions of the particular cell type. Photoreceptors detect light through a large, modified cilium (outer segment), that is supported by a surrounding ring of microvilli‐like calyceal processes (CPs). Although first reported 150 years ago, CPs remain poorly understood. As a basis for future study, we therefore conducted a review of existing literature about sensory cell microvilli, which can act either as the primary sensory detector or as support for a cilia‐based detector. While all microvilli are finger‐like cellular protrusions with an actin core, the processes vary across cell types in size, number, arrangement, dynamics, and function. We summarize the current state of knowledge about CPs and the characteristics of the microvilli found on inner ear hair cells (stereocilia) and cerebral spinal fluid‐contacting neurons, with comparisons to the brush border of the intestinal and renal epithelia. The structure, stability, and dynamics of the actin core are regulated by a complement of actin‐binding proteins, which includes both common components and unique features when compared across cell types. Further, microvilli are often supported by lateral links, a glycocalyx, and a defined extracellular matrix, each adapted to the function and environment of the cell. Our comparison of microvillar features will inform further research into how CPs support photoreceptor function, and also provide a general basis for investigations into the structure and functions of apical microvilli found on sensory neurons. This review compares microvilli across different types of sensory and epithelial cells, highlighting features of the actin cytoskeleton, interactions with cilia, intermicrovillar links, and associated glycocalyx.
... Cilia are evolutionarily conserved, microtubule-based organelles that are present on the surface of most cell types in vertebrates (1). The enrichment of various receptors and other ciliary exclusive proteins (2, 3) makes the cilium a unique organelle with critical roles in numerous developmental and fundamental physiological processes (4)(5)(6). Genetic defects of ciliary proteins that are necessary for cilia biogenesis, maintenance, and/or function can result in a broad class of human diseases and developmental disorders, termed ciliopathies (7). As a class of ciliopathies, Bardet-Biedl syndrome (BBS) can manifest as a constellation of symptoms including obesity, renal dysfunction, male infertility, skeletal malformation, cognitive defects, and retinal degeneration (8)(9)(10). ...
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Identification of molecular subtypes that reflect different prognoses and treatment responses, especially immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), is essential for treatment decisions. We performed targeted sequencing in 201 patients with ESCC to discover genetic subtypes and validate our findings via multiple data sets. We identified 3 driver genes (FCGBP, GRIN2B, and FRY), and recurrent truncating mutations in FRY impaired its tumor-suppressive function and promoted tumor proliferation. A 3-gene mutation signature (FAT1, FAT3, and FRY) recognized a molecular subtype named "FAT/FRY" with frequent Hippo pathway-related mutations. In multiple ESCC cohorts, the patients with the FAT/FRY subtype had poorer prognosis than did patients in the WT group. Transcriptome analysis indicated that the FAT/FRY subtype was characterized by inactivation of the Hippo pathway, hypoxia, chemoresistance, higher infiltration of CD8+ T cells and activated DCs, and a transcriptome similar to that of cancer responders. Furthermore, the 3-gene signature predicted better survival for patients treated with ICIs, partially explained by its positive correlation with the tumor mutation burden and neoantigen burden. The 3-gene signature is a biomarker to recognize the FAT/FRY molecular subtype, evaluate prognosis, and select potential beneficiaries of ICIs in ESCC.
... Cilia are evolutionarily conserved, microtubule-based organelles that are present on the surface of most cell types in vertebrates (1). The enrichment of various receptors and other ciliary exclusive proteins (2, 3) makes the cilium a unique organelle with critical roles in numerous developmental and fundamental physiological processes (4)(5)(6). Genetic defects of ciliary proteins that are necessary for cilia biogenesis, maintenance, and/or function can result in a broad class of human diseases and developmental disorders, termed ciliopathies (7). As a class of ciliopathies, Bardet-Biedl syndrome (BBS) can manifest as a constellation of symptoms including obesity, renal dysfunction, male infertility, skeletal malformation, cognitive defects, and retinal degeneration (8)(9)(10). ...
Article
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Ciliopathies are a class of genetic diseases resulting in cilia dysfunction in multiple organ systems, including the olfactory system. Currently, there are no available curative treatments for olfactory dysfunction and other symptoms in ciliopathies. The loss or shortening of olfactory cilia, as seen in multiple mouse models of the ciliopathy Bardet-Biedl syndrome (BBS), results in olfactory dysfunction. However, the underlying mechanism of the olfactory cilia reduction is unknown, thus limiting the development of therapeutic approaches for BBS and other ciliopathies. Here, we demonstrated that PI(4,5)P2, a phosphoinositide typically excluded from olfactory cilia, aberrantly redistributed into the residual cilia of BBS mouse models, which caused F-actin ciliary infiltration. Importantly, PI(4,5)P2 and F-actin were necessary for olfactory cilia shortening. Using a gene therapeutic approach, the hydrolyzation of PI(4,5)P2 by overexpression of INPP5E restored cilia length, and rescued odor detection and odor perception in BBS. Together, our data indicate that PI(4,5)P2 and F-actin-dependent cilia disassembly is a common mechanism contributing to the loss of olfactory cilia in BBS and provide valuable pan therapeutic intervention targets for the treatment of ciliopathies.
... Cilia, found on cell surfaces, are microtubule (MT)-based organelles that play essential roles for cell development, proliferation, differentiation, migration, signal transduction, etc. The structure, length, and function of cilia must be tightly regulated because their dysfunction is associated with numerous diseases collectively called ciliopathy disorders (Lee and Gleeson, 2011;Falk et al., 2015;Reiter and Leroux, 2017;Andreu-Cervera et al., 2021;Lee and Ostrowski, 2021). Based on their mobility, cilia are divided into two types: motile cilia and non-motile cilia like primary cilia. ...
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Kinocilia are exceptionally long primary sensory cilia located on vestibular hair cells, which are essential for transmitting key signals that contribute to mammalian balance and overall vestibular system function. Kinocilia have a “9+2” microtubule (MT) configuration with nine doublet MTs surrounding two central singlet MTs. This is uncommon as most mammalian primary sensory cilia have a “9+0” configuration, in which the central MT pair is absent. It has yet to be determined what the function of the central MT pair is in kinocilia. Calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) regulates the minus end of MTs and is essential for forming the central MT pair in motile cilia, which have the “9+2” configuration. To explore the role of the central MT pair in kinocilia, we created a conditional knockout model (cKO), Camsap3-cKO, which intended to eliminate CAMSAP3 in limited organs including the inner ear, olfactory bulb, and kidneys. Immunofluorescent staining of vestibular organs demonstrated that CAMSAP3 proteins were significantly reduced in Camsap3-cKO mice and that aged Camsap3-cKO mice had significantly shorter kinocilia than their wildtype littermates. Transmission electron microscopy showed that aged Camsap3-cKO mice were in fact missing that the central MT pair in kinocilia more often than their wildtype counterparts. In the examination of behavior, wildtype and Camsap3-cKO mice performed equally well on a swim assessment, right-reflex test, and evaluation of balance on a rotarod. However, Camsap3-cKO mice showed slightly altered gaits including reduced maximal rate of change of paw area and a smaller paw area in contact with the surface. Although Camsap3-cKO mice had no differences in olfaction from their wildtype counterparts, Camsap3-cKO mice did have kidney dysfunction that deteriorated their health. Thus, CAMSAP3 is important for establishing and/or maintaining the normal structure of kinocilia and kidney function but is not essential for normal olfaction. Our data supports our hypothesis that CAMSAP3 is critical for construction of the central MT pair in kinocilia, and that the central MT pair may be important for building long and stable axonemes in these kinocilia. Whether shorter kinocilia might lead to abnormal vestibular function and altered gaits in older Camsap3-cKO mice requires further investigation.
... In addition, the protein turnover in primary cilium of pancreatic b-cells in mice is not uniform. Arrojo E Drigo and collaborators showed that the basal body contained high 15 N levels, while the rest of the cilium was replaced by new components. These data suggest that long-lived structures are present in the basal body of b-cells leading to age mosaicism architecture within primary cilium (34). ...
... Main categories of cilia in humans(10)(11)(12)(13)(14)(15). ...
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The primary cilium is a narrow organelle located at the surface of the cell in contact with the extracellular environment. Once underappreciated, now is thought to efficiently sense external environmental cues and mediate cell-to-cell communication, because many receptors, ion channels, and signaling molecules are highly or differentially expressed in primary cilium. Rare genetic disorders that affect cilia integrity and function, such as Bardet-Biedl syndrome and Alström syndrome, have awoken interest in studying the biology of cilium. In this review, we discuss recent evidence suggesting emerging roles of primary cilium and cilia-mediated signaling pathways in the regulation of pancreatic β- and α-cell functions, and its implications in regulating glucose homeostasis.
... In photoreceptor cells (rods and cones), the sensory cilium is uniquely modified to accommodate a large amount of lightabsorbing molecules [3,4]. In the inner ear, an immotile kinocilium assembled by cochlear hair cells is accompanied by numerous highly organized actin-containing mechanosensory protrusions called stereocilia or stereovilli and plays a role in their proper arrangement [5,6]. In contrast to these monociliated cells, olfactory sensory neurons are multiciliated and form up to 10-30 olfactory cilia (that are usually 50-60 µm long) on the dendritic knob [5,7]. ...
... In the inner ear, an immotile kinocilium assembled by cochlear hair cells is accompanied by numerous highly organized actin-containing mechanosensory protrusions called stereocilia or stereovilli and plays a role in their proper arrangement [5,6]. In contrast to these monociliated cells, olfactory sensory neurons are multiciliated and form up to 10-30 olfactory cilia (that are usually 50-60 µm long) on the dendritic knob [5,7]. ...
... Photoreceptors can be morphologically and functionally divided into three compartments: (i) the most distal, light-sensitive outer segment, (ii) the organelle-containing (including cilium basal body) inner segment, and (iii) the connecting cilium, enabling transport between the inner and outer segments. In the connecting cilium, microtubules have a 9 × 2 + 0 organization, while in the outer segment, doublets are gradually reduced to singlets, and microtubules dislocate and lose the nine-fold symmetry [4,5]. Similarly, olfactory cilia have the 9 × 2 + 2 configuration in the proximal cilium, but peripheral doublets are reduced to singlets in the distal part (worthy of note is that these cilia are immotile as they lack dynein arms) [5,9]. ...
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Primary ciliary dyskinesia (PCD) is a hereditary genetic disorder caused by the lack of motile cilia or the assembxly of dysfunctional ones. This rare human disease affects 1 out of 10,000–20,000 individuals and is caused by mutations in at least 50 genes. The past twenty years brought significant progress in the identification of PCD-causative genes and in our understanding of the connections between causative mutations and ciliary defects observed in affected individuals. These scientific advances have been achieved, among others, due to the extensive motile cilia-related research conducted using several model organisms, ranging from protists to mammals. These are unicellular organisms such as the green alga Chlamydomonas, the parasitic protist Trypanosoma, and free-living ciliates, Tetrahymena and Paramecium, the invertebrate Schmidtea, and vertebrates such as zebrafish, Xenopus, and mouse. Establishing such evolutionarily distant experimental models with different levels of cell or body complexity was possible because both basic motile cilia ultrastructure and protein composition are highly conserved throughout evolution. Here, we characterize model organisms commonly used to study PCD-related genes, highlight their pros and cons, and summarize experimental data collected using these models.
... Through these cilium-dependent signaling pathways, primary cilia play key roles in the regulation of cell division, proliferation, and signal transduction and are thus crucial in tissue and organ development and normal mammalian physiology (Lancaster and Gleeson, 2009;Goetz and Anderson, 2010;Joukov and De Nicolo, 2019;Nachury and Mick, 2019). Moreover, primary cilia can act as a portal connecting the organism to the environment (Falk et al., 2015;Bujakowska et al., 2017;Uytingco et al., 2019;Ran and Zhou, 2020). ...
... Some primary cilia with specialized structures and functions have been characterized in sensory cells, which can transduce external physical or chemical signals, such as smell and visual signals, to electrical signals in mammalian olfactory and vision systems (Falk et al., 2015). Kinocilia are specialized primary cilia present in auditory hair cells (HCs) in the inner ear. ...
Article
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Primary cilia are evolutionarily conserved and highly specialized organelles that protrude from cell membranes. Mutations in genes encoding ciliary proteins can cause structural and functional ciliary defects and consequently multiple diseases, collectively termed ciliopathies. The mammalian auditory system is responsible for perceiving external sound stimuli that are ultimately processed in the brain through a series of physical and biochemical reactions. Here we review the structure and function of the specialized primary cilia of hair cells, termed kinocilia, found in the mammalian auditory system. We also discuss areas that might prove amenable for therapeutic management of auditory ciliopathies.
... Cilia adopt specialized structures when it comes to perception of sensory signals [31]. Vertebrate photoreceptor cells possess a specialized primary cilium restructured as the so-called outer segment consisting of tightly packed membrane discs. ...
... In addition, the outer segment is connected to the inner segment by a so-called connecting cilium, thought to represent a modified transition zone. The constant movement of signaling molecules through the connecting cilium as well as transport of "debris" back to the cell body is essential for the proper function of photoreceptor cells [31]. Primary cilia in olfactory neuronal cilia adorned with GPCR signal receptors enable perception of smell by enhancing the expression of adenylate cyclase III in neurons via GPCR signaling [31]. ...
... The constant movement of signaling molecules through the connecting cilium as well as transport of "debris" back to the cell body is essential for the proper function of photoreceptor cells [31]. Primary cilia in olfactory neuronal cilia adorned with GPCR signal receptors enable perception of smell by enhancing the expression of adenylate cyclase III in neurons via GPCR signaling [31]. The single kinocilium located on mammalian hair cells is important for establishing the polarity of stereocilia or sterovilli bundles and hence contributing towards the hearing process in mammals [32]. ...
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Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.
... Interestingly, in mice, CFAP69 is also present in the immotile olfactory cilia of the olfactory sensory neurons (OSN) 38 . The OSN cilia can be divided into two segments, proximal containing a CA (9 × 2 + 2) and distal with a decreasing number of microtubules (from 9 × 1 to 4 × 1) 39 . It will be of interest to determine whether in the OSN cilia CFAP69 is present only in the CA-containing proximal fragment or along the entire cilia length, suggesting another intraciliary localization and likely function in these sensory cilia. ...
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Motile cilia are ultrastructurally complex cell organelles with the ability to actively move. The highly conserved central apparatus of motile 9 × 2 + 2 cilia is composed of two microtubules and several large microtubule-bound projections, including the C1b/C1f supercomplex. The composition and function of C1b/C1f subunits has only recently started to emerge. We show that in the model ciliate Tetrahymena thermophila , C1b/C1f contains several evolutionarily conserved proteins: Spef2A, Cfap69, Cfap246/LRGUK, Adgb/androglobin, and a ciliate-specific protein Tt170/TTHERM_00205170. Deletion of genes encoding either Spef2A or Cfap69 led to a loss of the entire C1b projection and resulted in an abnormal vortex motion of cilia. Loss of either Cfap246 or Adgb caused only minor alterations in ciliary motility. Comparative analyses of wild-type and C1b-deficient mutant ciliomes revealed that the levels of subunits forming the adjacent C2b projection but not C1d projection are greatly reduced, indicating that C1b stabilizes C2b. Moreover, the levels of several IFT and BBS proteins, HSP70, and enzymes that catalyze the final steps of the glycolytic pathway: enolase ENO1 and pyruvate kinase PYK1, are also reduced in the C1b-less mutants.