Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction

McKenzie, Casey W.; Preston, Claudia C.; Finn, Rozzy; Eyster, Kathleen M.; Faustino, Randolph S.; Lee, Lance

doi:10.1038/s41598-018-31743-5

Cited by 22 publications

(19 citation statements)

References 90 publications

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“…Cilia-related diseases, otherwise known as ciliopathies, such as primary ciliary dyskinesia (PCD), are derived from the impairment of motile cilia [5,6]. Patients who suffer from PCD often experience a wide spectrum of symptoms ranging from male infertility to an increased susceptibility to respiratory infections [7].…”

Section: Introductionmentioning

confidence: 99%

Identification and mapping of central pair proteins by proteomic analysis

et al. 2020

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Proteomic exploration of the central pair Cilia and flagella are highly organized structures of eukaryotes which propel the cell motions or generate liquid flows around the cells. The central pair complex is located at the center of cilia and flagella. It is known to be essential for the regulation of beating of cilia and flagella, but its protein composition and architecture were poorly understood. By exploiting comprehensive mass spectrometry and several mutant strains of Chlamydomonas, we identified novel central pair proteins and mapped these proteins to the structure. Our model can be used as a foundation to understand the functions of the central pair complex.

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Section: Introductionmentioning

confidence: 99%

Identification and mapping of central pair proteins by proteomic analysis

et al. 2020

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“…1). Homozygotes with either the nm1054, bgh, or Cfap54 gt/gt mutation exhibit early mortality on the B6 background due to severe hydrocephalus, presumably due to genetic modifiers segregating in that strain that influence susceptibility to severe hydrocephalus 26,27,29,30,38 . On the 129 background or a mixed background, single homozygotes do not develop severe hydrocephalus and live a normal life span, despite exhibiting airway ciliary phenotypes and male infertility.…”

Section: Discussionmentioning

confidence: 99%

Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia

McKenzie

Lee

2020

Sci Rep

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primary ciliary dyskinesia (pcD) is a genetically heterogeneous syndrome that results from defects in motile cilia. The ciliary axoneme has a 9 + 2 microtubule structure consisting of nine peripheral doublets surrounding a central pair apparatus (CPA), which plays a critical role in regulating proper ciliary function. We have previously shown that mouse models with mutations in cpA genes CFAP221, CFAP54, and SPEF2 have a PCD phenotype with defects in ciliary motility. In this study, we investigated potential genetic interaction between these cpA genes by generating each combination of double heterozygous and double homozygous mutants. no detectable cilia-related phenotypes were observed in double heterozygotes, but all three double homozygous mutant lines exhibit early mortality and typically develop severe PCD-associated phenotypes of hydrocephalus, mucociliary clearance defects in the upper airway, and abnormal spermatogenesis. Double homozygous cilia are generally intact and display a normal morphology and distribution. Spermiogenesis is aborted in double homozygotes, with an absence of mature flagella on elongating spermatids and epididymal sperm. These findings identify genetic interactions between CPA genes and genetic mechanisms regulating the cpA and motile cilia function. Primary ciliary dyskinesia (PCD) is a syndrome resulting from dysfunction of motile ciliary clearance in the respiratory system, the brain, the fallopian tube, and the embryonic node, as well as sperm flagellar motility 1-5. It is genetically heterogeneous and commonly inherited in an autosomal recessive manner, although mutations causing X-linked recessive and autosomal dominant inheritance have been reported 6-9. Approximately 1 in 16,000 children are affected and typically exhibit chronic upper and lower airway infection, otitis media, male infertility, and situs inversus. Neonatal respiratory distress, congenital heart defects, female infertility, and hydrocephalus are also associated at a lower frequency. The core, or axoneme, of the motile cilium has a 9 + 2 microtubule structure with nine doublets along the outer periphery surrounding a central pair apparatus (CPA) 4,10. Ciliary motility is generated by dynein arms associated with the outer microtubule doublets and is regulated by the CPA, radial spokes connecting the outer and central microtubules, and the dynein regulatory complex. The cilia on the embryonic node possess a 9 + 0 microtubule structure without a CPA. A substantial number of mouse models of PCD has helped uncover the role of novel genes in ciliary function and PCD pathogenesis 4,5. However, only a few studies have investigated epistatic interaction of these genes. Mice lacking dynein assembly factor coiled coil domain containing protein 40 (CCDC40) have situs inversus with randomized expression of left-right patterning marker NODAL during gastrulation 11,12. Homozygous mutants that are also heterozygous for a NODAL mutation fail to establish left isomerism or left-sided expression of NODAL 12 , demonstrating that ...

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“…These studies suggest that the 129 background can be used to overcome premature lethality caused by hydrocephalus. However, genetic modifiers that segregate these strains remain unknown [ 34 ], and it is still unclear if the 129 background can rescue all cases. For example, Spag6 (sperm associated antigen 6), a mouse ortholog of Chlamydomonas PF16 that contains armadillo repeats and is associated with the C1 microtubule [ 56 ], was mutated on the mixed background (C57BL/6-129/Sv); however, about 50% of the Spag6 KO mice died from hydrocephalus before 2 months of age [ 51 ].…”

Section: Analysis Of Mature Spermatozoa Using 129 Backgroundsmentioning

confidence: 99%

Analysis of the sperm flagellar axoneme using gene-modified mice

2020

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Infertility is a global health issue that affects 1 in 6 couples, with male factors contributing to 50% of cases. The flagellar axoneme is a motility apparatus of spermatozoa, and disruption of its structure or function could lead to male infertility. The axoneme consists of a “9+2” structure that contains a central pair of two singlet microtubules surrounded by nine doublet microtubules, in addition to several macromolecular complexes such as dynein arms, radial spokes, and nexin-dynein regulatory complexes. Molecular components of the flagellar axoneme are evolutionally conserved from unicellular flagellates to mammals, including mice. Although knockout (KO) mice have been generated to understand their function in the formation and motility regulation of sperm flagella, the majority of KO mice die before sexual maturation due to impaired ciliary motility, which makes it challenging to analyze mature spermatozoa. In this review, we introduce methods that have been used to overcome premature lethality, focusing on KO mouse lines of central pair components.

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Strain-specific differences in brain gene expression in a hydrocephalic mouse model with motile cilia dysfunction

Cited by 22 publications

References 90 publications

Identification and mapping of central pair proteins by proteomic analysis

Identification and mapping of central pair proteins by proteomic analysis

Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia

Analysis of the sperm flagellar axoneme using gene-modified mice

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