Mammalian axoneme central pair complex proteins: Broader roles revealed by gene knockout phenotypes

Teves, María E.; Nagarkatti-Gude, David R.; Zhang, Zhibing; Strauss, Jerome F.

doi:10.1002/cm.21271

Cited by 53 publications

(51 citation statements)

References 107 publications

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“…Three‐dimensional structured illumination microscopy (3D‐SIM) further revealed that Rsph9 was specifically located in the lumen formed by the 9 MT doublets, marked by acetylated tubulin (Figure E). Distributions of the Rsph9 immunofluorescence were slightly wider than those of hydin, a CP apparatus marker [Lechtreck and Witman, ; Lechtreck et al., ; Teves et al., ] (Figure E), supporting its role as an RS subunit. Consistent to the immunoblotting results (Figure B), Rsph9 was not detected in primary cilium (Figure F).…”

Section: Resultsmentioning

confidence: 84%

Rsph9 is critical for ciliary radial spoke assembly and central pair microtubule stability

Zhu

Líu

Chen

et al. 2018

Biology of the Cell

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Background Information In the “9+2”‐type motile cilia, radial spokes (RSs) protruded from the nine peripheral microtubule doublets surround and interact with the central pair (CP) apparatus to regulate ciliary beat. RSPH9 is the human homologue of the essential protozoan RS head protein Rsp9. Its mutations in human primary ciliary dyskinesia patients, however, cause CP loss in a small portion of airway cilia without affecting the ciliary localization of other head proteins. Results We characterized mouse Rsph9 and investigated its function in ependymal motile cilia. Rsph9 was specifically expressed in mouse tissues containing motile cilia and upregulated during multiciliation. Its ciliary localization complied with its putative role as an RS subunit. Depletion of Rsph9 by RNAi in mouse ependymal cilia resulted in a near complete CP loss and altered the ciliary beat pattern from planar to rotational. Multiple RS proteins, including those in the head, were also markedly downregulated in the Rsph9‐depleted cilia. Conclusion Rsph9 is essential for both the RS head assembly and the CP maintenance in mammalian ependymal cilia. Significance Our results help to understand the assembly and functions of mammalian RS and pathology of RS‐related ciliopathy.

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Section: Resultsmentioning

confidence: 84%

Rsph9 is critical for ciliary radial spoke assembly and central pair microtubule stability

Zhu

Líu

Chen

et al. 2018

Biology of the Cell

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“…Additionally, we found two top candidates in CEU that have not been explicitly described as sweeps previously, RSPH3 and ZNF211 (both m = 1). RSPH3 encodes a radial spoke protein that is integral in the structure of 9 + 2 motile cilia across diverse cell types, including flagellated cells [Teves et al, 2016], and so selection here may be related to ancient sperm competition in humans [Leivers et al, 2014]. ZNF211 is among a diverse set of zinc-finger genes whose products are believed to participate in the inactivation of endogenous retroviruses, parasitic mobile DNA whose effects can be deleterious to their hosts [Lukic et al, 2014].…”

Section: Application To Empirical Datasetsmentioning

confidence: 99%

A likelihood approach for uncovering selective sweep signatures from haplotype data

Harris

DeGiorgio

2019

Preprint

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AbstractSelective sweeps are frequent and varied signatures in the genomes of natural populations, and detecting them is consequently important in understanding mechanisms of adaptation by natural selection. Following a selective sweep, haplotypic diversity surrounding the site under selection decreases, and this deviation from the background pattern of variation can be applied to identify sweeps. Multiple methods exist to locate selective sweeps in the genome from haplotype data, but none leverage the power of a model-based approach to make their inference. Here, we propose a likelihood ratio test statistic T to probe whole genome polymorphism datasets for selective sweep signatures. Our framework uses a simple but powerful model of haplotype frequency spectrum distortion to find sweeps and additionally make an inference on the number of presently sweeping haplotypes in a population. We found that the T statistic is suitable for detecting both hard and soft sweeps across a variety of demographic models, selection strengths, and ages of the beneficial allele. Accordingly, we applied the T statistic to variant calls from European and sub-Saharan African human populations, yielding primarily literature-supported candidates, including LCT, RSPH3, and ZNF211 in CEU, SYT1, RGS18, and NNT in YRI, and HLA genes in both populations. We also searched for sweep signatures in Drosophila melanogaster, finding expected candidates at Ace, Uhg1, and Pimet. Finally, we provide open-source software to compute the T statistic and the inferred number of presently sweeping haplotypes from whole-genome data.

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“…9 Previous studies on genetic mutants in model organisms have revealed genetic contributions to flagellar motility defects. 2,[10][11][12][13][14] So far, mutations in only three genes, AKAP4 (MIM: 300185), CCDC39 (MIM: 613798), and DNAH1 (MIM: 603332), have been formally identified to cause MMAF in humans. 2,3,15,16 Among them, biallelic DNAH1 mutations in MMAF have been recurrently identified across studies and account for 28%-44% of MMAF cases.…”

Section: Introductionmentioning

confidence: 99%

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

Tang¹,

Wang

Li³

et al. 2017

The American Journal of Human Genetics

256

212

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Sperm motility is vital to human reproduction. Malformations of sperm flagella can cause male infertility. Men with multiple morphological abnormalities of the flagella (MMAF) have abnormal spermatozoa with absent, short, coiled, bent, and/or irregular-caliber flagella, which impair sperm motility. The known human MMAF-associated genes, such as DNAH1, only account for fewer than 45% of affected individuals. Pathogenic mechanisms in the genetically unexplained MMAF remain to be elucidated. Here, we conducted genetic analyses by using whole-exome sequencing and genome-wide comparative genomic hybridization microarrays in a multi-center cohort of 30 Han Chinese men affected by MMAF. Among them, 12 subjects could not be genetically explained by any known MMAFassociated genes. Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations. CFAP43 and CFAP44, encoding two cilia-and flagella-associated proteins (CFAPs), are specifically or preferentially expressed in the testis. Using CRISPR/Cas9 technology, we generated two knockout models each deficient in mouse ortholog Cfap43 or Cfap44. Notably, both Cfap43-and Cfap44-deficient male mice presented with MMAF phenotypes, whereas the corresponding female mice were fertile. Our experimental observations on human subjects and animal models strongly suggest that biallelic mutations in either CFAP43 or CFAP44 can cause sperm flagellar abnormalities and impair sperm motility. Further investigations on other CFAP-encoding genes in more genetically unexplained MMAF-affected individuals could uncover novel mechanisms underlying sperm flagellar formation.

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Mammalian axoneme central pair complex proteins: Broader roles revealed by gene knockout phenotypes

Cited by 53 publications

References 107 publications

Rsph9 is critical for ciliary radial spoke assembly and central pair microtubule stability

Rsph9 is critical for ciliary radial spoke assembly and central pair microtubule stability

A likelihood approach for uncovering selective sweep signatures from haplotype data

Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella

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