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Disease Models & Mechanisms May 2024Vertebrate photoreceptors are highly specialized retinal neurons that have cilium-derived membrane organelles called outer segments (OS), which function as platforms for...
Vertebrate photoreceptors are highly specialized retinal neurons that have cilium-derived membrane organelles called outer segments (OS), which function as platforms for phototransduction. Male germ cell-associated kinase (MAK) is a cilium-associated serine/threonine kinase, and its genetic mutation causes photoreceptor degeneration in mice and retinitis pigmentosa in humans. However, the role of MAK in photoreceptors is not fully understood. Here, we report that zebrafish mak mutants show rapid photoreceptor degeneration during embryonic development. In mak mutants, both cone and rod photoreceptors completely lack OSs and undergo apoptosis. Interestingly, zebrafish mak mutants fail to generate axonemes during photoreceptor ciliogenesis, whereas basal bodies are specified. These data suggest that MAK contributes to axoneme development in zebrafish, in contrast to mouse Mak mutants, which have elongated photoreceptor axonemes. Furthermore, the kinase activity of MAK is critical in ciliary axoneme development and photoreceptor survival. Thus, MAK is required for ciliogenesis and OS formation in zebrafish photoreceptors to ensure intracellular protein transport and photoreceptor survival.
PubMed: 38813692
DOI: 10.1242/dmm.050618 -
Journal of Physiological Investigation Mar 2024Uterine adenomyosis is an estrogen-dependent chronic inflammatory condition and may cause painful symptoms, abnormal uterine bleeding, and/or subfertility/infertility.... (Review)
Review
Uterine adenomyosis is an estrogen-dependent chronic inflammatory condition and may cause painful symptoms, abnormal uterine bleeding, and/or subfertility/infertility. It is characterized by the presence of endometrial glands and stroma within the myometrium causing enlargement of the uterus as a result of reactive hyperplastic and/or hypertrophic change of the surrounding myometrium. Similar to endometriosis, adenomyosis has a negative impact on female fertility. Abnormal uterotubal sperm transport, tissue inflammation, and the toxic effect of chemical mediators have been proposed as contributing factors. Inflammation-induced damage of the mucosal cilia in the fallopian tube has been reported. Besides other proposed mechanisms, our most recent study with transmission electron microscopy analysis indicated that microvilli damage and an axonemal alteration in the apical endometria occur in response to endometrial inflammation. This may be involved in the negative fertility outcome in women with adenomyosis. We present a critical analysis of the literature data concerning the mechanistic basis of infertility in women with adenomyosis and its impact on fertility outcome.
Topics: Humans; Female; Adenomyosis; Infertility, Female; Endometrium; Cilia
PubMed: 38780290
DOI: 10.4103/ejpi.EJPI-D-24-00032 -
EMBO Reports May 2024Alpha, beta, and gamma tubulins are essential building blocks for all eukaryotic cells. The functions of the non-canonical tubulins, delta, epsilon, and zeta, however,...
Alpha, beta, and gamma tubulins are essential building blocks for all eukaryotic cells. The functions of the non-canonical tubulins, delta, epsilon, and zeta, however, remain poorly understood and their requirement in mammalian development untested. Herein we have used a spermatogenesis model to define epsilon tubulin (TUBE1) function in mice. We show that TUBE1 is essential for the function of multiple complex microtubule arrays, including the meiotic spindle, axoneme and manchette and in its absence, there is a dramatic loss of germ cells and male sterility. Moreover, we provide evidence for the interplay between TUBE1 and katanin-mediated microtubule severing, and for the sub-specialization of individual katanin paralogs in the regulation of specific microtubule arrays.
PubMed: 38773322
DOI: 10.1038/s44319-024-00159-w -
The Journal of Biological Chemistry May 2024Motile cilia on the cell surface produce fluid flows in the body and abnormalities in motile cilia cause primary ciliary dyskinesia (PCD). Dynein axonemal assembly...
Motile cilia on the cell surface produce fluid flows in the body and abnormalities in motile cilia cause primary ciliary dyskinesia (PCD). Dynein axonemal assembly factors 6 (DNAAF6), a causative gene of PCD, was isolated as an interacting protein with La ribonucleoprotein 6 (LARP6) that regulates ciliogenesis in multi-ciliated cells (MCCs). In MCCs of Xenopus embryos, LARP6 and DNAAF6 were co-localized in biomolecular condensates termed dynein axonemal particles (DynAPs) and synergized to control ciliogenesis. Moreover, Tubulin alpha 1c like (TUBA1CL) mRNA encoding α-Tubulin protein that is a major component of ciliary axoneme was identified as a target mRNA regulated by binding LARP6. While DNAAF6 was necessary for high α-Tubulin protein expression near the apical side of Xenopus MCCs during ciliogenesis, its mutant, which abolishes binding with LARP6, was unable to restore the expression of α-Tubulin protein near the apical side of MCCs in Xenopus DNAAF6 morphant. These results indicated that the binding of LARP6 and DNAAF6 in DynAPs regulates highly expressed α-Tubulin protein near the apical side of Xenopus MCCs during ciliogenesis.
PubMed: 38762183
DOI: 10.1016/j.jbc.2024.107373 -
Cellular & Molecular Biology Letters May 2024By analyzing a mouse Interspecific Recombinant Congenic Strain (IRCS), we previously identified a quantitative trait locus (QTL), called Mafq1 on mouse chromosome 1,...
By analyzing a mouse Interspecific Recombinant Congenic Strain (IRCS), we previously identified a quantitative trait locus (QTL), called Mafq1 on mouse chromosome 1, that is associated with male hypofertility and ultrastructural sperm abnormalities. Within this locus, we identified a new candidate gene that could be implicated in a reproductive phenotype: Tex44 (Testis-expressed protein 44). We thus performed a CRISPR/Cas9-mediated complete deletion of this gene in mice in order to study its function. Tex44-KO males were severely hypofertile in vivo and in vitro due to a drastic reduction of sperm motility which itself resulted from important morphological sperm abnormalities. Namely, Tex44-KO sperm showed a disorganized junction between the midpiece and the principal piece of the flagellum, leading to a 180° flagellar bending in this region. In addition, the loss of some axonemal microtubule doublets and outer dense fibers in the flagellum's principal piece has been observed. Our results suggest that, in mice, TEX44 is implicated in the correct set-up of the sperm flagellum during spermiogenesis and its absence leads to flagellar abnormalities and consequently to severe male hypofertility.
Topics: Animals; Male; Infertility, Male; Sperm Motility; Sperm Tail; Mice; Mice, Knockout; Spermatozoa; Spermatogenesis; Flagella; Mice, Inbred C57BL; CRISPR-Cas Systems
PubMed: 38750428
DOI: 10.1186/s11658-024-00587-5 -
BMC Genomics May 2024The severity of COVID-19 is influenced by various factors including the presence of respiratory diseases. Studies have indicated a potential relationship between asthma...
BACKGROUND
The severity of COVID-19 is influenced by various factors including the presence of respiratory diseases. Studies have indicated a potential relationship between asthma and COVID-19 severity.
OBJECTIVE
This study aimed to conduct a genome-wide association study (GWAS) to identify genetic and clinical variants associated with the severity of COVID-19, both among patients with and without asthma.
METHODS
We analyzed data from 2131 samples sourced from the Biobanque québécoise de la COVID-19 (BQC19), with 1499 samples from patients who tested positive for COVID-19. Among these, 1110 exhibited mild-to-moderate symptoms, 389 had severe symptoms, and 58 had asthma. We conducted a comparative analysis of clinical data from individuals in these three groups and GWAS using a logistic regression model. Phenotypic data analysis resulted in the refined covariates integrated into logistic models for genetic studies.
RESULTS
Considering a significance threshold of 1 × 10, seven genetic variants were associated with severe COVID-19. These variants were located proximal to five genes: sodium voltage-gated channel alpha subunit 1 (SCN10A), desmoplakin (DSP), RP1 axonemal microtubule associated (RP1), IGF like family member 1 (IGFL1), and docking protein 5 (DOK5). The GWAS comparing individuals with severe COVID-19 with asthma to those without asthma revealed four genetic variants in transmembrane protein with EGF like and two follistatin like domains 2 (TMEFF2) and huntingtin interacting protein-1 (HIP1) genes.
CONCLUSION
This study provides significant insights into the genetic profiles of patients with severe forms of the disease, whether accompanied by asthma or not. These findings enhance our comprehension of the genetic factors that affect COVID-19 severity.
KEY MESSAGES
Seven genetic variants were associated with the severe form of COVID-19; Four genetic variants were associated with the severe form of COVID-19 in individuals with comorbid asthma; These findings help define the genetic component of the severe form of COVID-19 in relation to asthma as a comorbidity.
Topics: Humans; COVID-19; Asthma; Genome-Wide Association Study; Male; Female; Middle Aged; SARS-CoV-2; Comorbidity; Adult; Severity of Illness Index; Cohort Studies; Polymorphism, Single Nucleotide; Aged; Genomics; Genetic Predisposition to Disease
PubMed: 38750426
DOI: 10.1186/s12864-024-10342-x -
Current Biology : CB May 2024A primary cilium is a membrane-bound extension from the cell surface that contains receptors for perceiving and transmitting signals that modulate cell state and...
A primary cilium is a membrane-bound extension from the cell surface that contains receptors for perceiving and transmitting signals that modulate cell state and activity. Primary cilia in the brain are less accessible than cilia on cultured cells or epithelial tissues because in the brain they protrude into a deep, dense network of glial and neuronal processes. Here, we investigated cilia frequency, internal structure, shape, and position in large, high-resolution transmission electron microscopy volumes of mouse primary visual cortex. Cilia extended from the cell bodies of nearly all excitatory and inhibitory neurons, astrocytes, and oligodendrocyte precursor cells (OPCs) but were absent from oligodendrocytes and microglia. Ultrastructural comparisons revealed that the base of the cilium and the microtubule organization differed between neurons and glia. Investigating cilia-proximal features revealed that many cilia were directly adjacent to synapses, suggesting that cilia are poised to encounter locally released signaling molecules. Our analysis indicated that synapse proximity is likely due to random encounters in the neuropil, with no evidence that cilia modulate synapse activity as would be expected in tetrapartite synapses. The observed cell class differences in proximity to synapses were largely due to differences in external cilia length. Many key structural features that differed between neuronal and glial cilia influenced both cilium placement and shape and, thus, exposure to processes and synapses outside the cilium. Together, the ultrastructure both within and around neuronal and glial cilia suggest differences in cilia formation and function across cell types in the brain.
PubMed: 38749425
DOI: 10.1016/j.cub.2024.04.043 -
BioRxiv : the Preprint Server For... Apr 2024Proper connection between the sperm head and tail is critical for sperm motility and fertilization. The link between the head and tail is mediated by the Head-Tail...
Proper connection between the sperm head and tail is critical for sperm motility and fertilization. The link between the head and tail is mediated by the Head-Tail Coupling Apparatus (HTCA), which secures the axoneme (tail) to the nucleus (head). However, the molecular architecture of the HTCA is not well understood. Here, we use to create a high-resolution map of proteins and structures at the HTCA throughout spermiogenesis. Using structured illumination microscopy, we demonstrate that key HTCA proteins Spag4 and Yuri form a 'Centriole Cap' that surrounds the centriole (or Basal Body) as it is inserted, or embedded into the surface of the nucleus. As development progresses, the centriole is laterally displaces to the side of the nucleus, during which time the HTCA expands under the nucleus, forming what we term the 'Nuclear Shelf.' We next show that the proximal centriole-like (PCL) structure is positioned under the Nuclear Shelf and functions as a critical stabilizer of the centriole-nuclear attachment. Together, our data indicate that the HTCA is complex, multi-point attachment site that simultaneously engages the PCL, the centriole, and the nucleus to ensure proper head-tail connection during late-stage spermiogenesis.
PubMed: 38712096
DOI: 10.1101/2024.04.15.589606 -
Journal of Cell Science May 2024DPF3, along with other subunits, is a well-known component of the BAF chromatin remodeling complex, which plays a key role in regulating chromatin remodeling activity...
DPF3, along with other subunits, is a well-known component of the BAF chromatin remodeling complex, which plays a key role in regulating chromatin remodeling activity and gene expression. Here, we elucidated a non-canonical localization and role for DPF3. We showed that DPF3 dynamically localizes to the centriolar satellites in interphase and to the centrosome, spindle midzone and bridging fiber area, and midbodies during mitosis. Loss of DPF3 causes kinetochore fiber instability, unstable kinetochore-microtubule attachment and defects in chromosome alignment, resulting in altered mitotic progression, cell death and genomic instability. In addition, we also demonstrated that DPF3 localizes to centriolar satellites at the base of primary cilia and is required for ciliogenesis by regulating axoneme extension. Taken together, these findings uncover a moonlighting dual function for DPF3 during mitosis and ciliogenesis.
Topics: Mitosis; Cilia; Humans; Centrioles; Transcription Factors; Kinetochores; DNA-Binding Proteins; Animals; Mice; Genomic Instability; Centrosome; Spindle Apparatus; HeLa Cells; Axoneme
PubMed: 38661008
DOI: 10.1242/jcs.261744 -
Nature Communications Apr 2024Intraflagellar transport (IFT) orchestrates entry of proteins into primary cilia. At the ciliary base, assembled IFT trains, driven by kinesin-2 motors, can transport...
Intraflagellar transport (IFT) orchestrates entry of proteins into primary cilia. At the ciliary base, assembled IFT trains, driven by kinesin-2 motors, can transport cargo proteins into the cilium, across the crowded transition zone. How trains assemble at the base and how proteins associate with them is far from understood. Here, we use single-molecule imaging in the cilia of C. elegans chemosensory neurons to directly visualize the entry of kinesin-2 motors, kinesin-II and OSM-3, as well as anterograde cargo proteins, IFT dynein and tubulin. Single-particle tracking shows that IFT components associate with trains sequentially, both in time and space. Super-resolution maps of IFT components in wild-type and mutant worms reveal ciliary ultrastructure and show that kinesin-II is essential for axonemal organization. Finally, imaging cilia lacking kinesin-II and/or transition zone function uncovers the interplay of kinesin-II and OSM-3 in driving efficient transport of IFT trains across the transition zone.
Topics: Caenorhabditis elegans; Animals; Cilia; Caenorhabditis elegans Proteins; Kinesins; Flagella; Tubulin; Axoneme; Dyneins; Biological Transport; Single Molecule Imaging; Protein Transport
PubMed: 38658528
DOI: 10.1038/s41467-024-47807-2