Motile cilia genetics and cell biology: big results from little mice

Lee, Lance; Ostrowski, Lawrence E.

doi:10.1007/s00018-020-03633-5

Cited by 35 publications

(30 citation statements)

References 318 publications

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“…In humans, mutations in several genes encoding components of the CA cause primary ciliary dyskinesia (PCD) or more frequently, multiple morphological abnormalities of the sperm flagella (MMAF) syndrome 33 , 34 . Recent genetic analysis using whole-exome sequencing identified homozygous stop-gain mutation in CFAP69 (p.Gln255X 35 ) and SPEF2 (p.Arg304X 36 ) as likely MMAF causal mutations.…”

Section: Resultsmentioning

confidence: 99%

Composition and function of the C1b/C1f region in the ciliary central apparatus

Joachimiak

Osinka

Farahat

et al. 2021

Sci Rep

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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.

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Section: Resultsmentioning

confidence: 99%

Composition and function of the C1b/C1f region in the ciliary central apparatus

Joachimiak

Osinka

Farahat

et al. 2021

Sci Rep

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“…Lastly, we found that UNC-45A is abundantly expressed in both the ciliated columnar epithelium of the fallopian tube and the cilia of the ependymocytes. Interestingly, congenital loss-of-function mutations in UNC-45A cause a syndrome characterized by diarrhea, cholestasis, bone fragility, and impaired hearing [ 56 ], all of which symptoms involve organs where cilia play important roles in physiology [ 57 , 58 , 59 ]. Furthermore, almost all of the subjects affected by congenital UNC-45A loss have signs of intellectual disability [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

Clemente

Hoshino

Meints

et al. 2021

Cells

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UNC-45A (Protein unc-45 homolog A) is a cytoskeletal-associated protein with a dual and non-mutually exclusive role as a regulator of the actomyosin system and a Microtubule (MT)-destabilizing protein, which is overexpressed in human cancers including in ovarian cancer patients resistant to the MT-stabilizing drug paclitaxel. Mapping of UNC-45A in the mouse upper genital tract and central nervous system reveals its enrichment not only in highly proliferating and prone to remodeling cells, but also in microtubule-rich areas, of the ovaries and the nervous system, respectively. In both apparatuses, UNC-45A is also abundantly expressed in the ciliated epithelium. As regulators of actomyosin contractility and MT stability are essential for the physiopathology of the female reproductive tract and of neuronal development, our findings suggest that UNC-45A may have a role in ovarian cancer initiation and development as well as in neurodegeneration.

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“…Interestingly, DNAH11 mutant mice have immotile respiratory cilia in contrast to humans, where cilia motility is not entirely abrogated but a rather stiff high frequency beating pattern can be observed [103,180]. Likewise, while the majority of PCD mouse models develop hydrocephalus causing high lethality, human PCD patients rarely do [181].…”

Section: Axonemal Dynein Related Ciliopathiesmentioning

confidence: 99%

Ciliary Dyneins and Dynein Related Ciliopathies

Antony

Brunner

Schmidts

2021

Cells

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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.

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Motile cilia genetics and cell biology: big results from little mice

Cited by 35 publications

References 318 publications

Composition and function of the C1b/C1f region in the ciliary central apparatus

Composition and function of the C1b/C1f region in the ciliary central apparatus

UNC-45A Is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

Ciliary Dyneins and Dynein Related Ciliopathies

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