Male Infertility, Impaired Sperm Motility, and Hydrocephalus in Mice Deficient in Sperm-Associated Antigen 6

Center for Research on Reproduction and Women's Health, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 10/2002; 22(17):6298-305. DOI: 10.1128/MCB.22.17.6298-6305.2002
Source: PubMed


Gene targeting was used to create mice lacking sperm-associated antigen 6 (Spag6), the murine orthologue of Chlamydomonas PF16, an axonemal protein containing eight armadillo repeats predicted to be important for flagellar motility and stability
of the axoneme central apparatus. Within 8 weeks of birth, approximately 50% of Spag6-deficient animals died with hydrocephalus.
Spag6-deficient males surviving to maturity were infertile. Their sperm had marked motility defects and was morphologically
abnormal with frequent loss of the sperm head and disorganization of flagellar structures, including loss of the central pair
of microtubules and disorganization of the outer dense fibers and fibrous sheath. We conclude that Spag6 is essential for
sperm flagellar motility and that it is important for the maintenance of the structural integrity of mature sperm. The occurrence
of hydrocephalus in the mutant mice also implicates Spag6 in the motility of ependymal cilia.

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    • "Hydrocephalus, also called " water on the brain " , is an abnormal medical condition caused by accumulation of the CSF in the ventricles due to a blockage of the CSF outflow or as a result of excessive CSF production (Oreskovic and Klarica, 2011). Mutations in ciliary components that affect the generation or beating of cilia cause ventricular enlargement and hydrocephalus (Banizs et al., 2005; Ibanez-Tallon et al., 2004; Lechtreck et al., 2008; Sapiro et al., 2002). Hydrocephalus resulting from an obstruction along one or more of the narrow passages connecting the ventricles is classified as non-communicating hydrocephalus , whereas hydrocephalus due to impaired absorption of the CSF in the subarachnoid space is termed as communicating hydrocephalus (Perez-Figares et al., 2001). "
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    ABSTRACT: Cerebrospinal fluid (CSF) is produced by the choroid plexus and moved by multi-ciliated ependymal cells through the ventricular system of the vertebrate brain. Defects in the ependymal layer functionality are a common cause of hydrocephalus. N-WASP (Neural-Wiskott Aldrich Syndrome Protein) is a brain-enriched regulator of actin cytoskeleton and N-WASP knockout caused embryonic lethality in mice with neural tube and cardiac abnormalities. To shed light on the role of N-WASP in mouse brain development, we generated N-WASP conditional knockout mouse model N-WASP(fl/fl); Nestin-Cre (NKO-Nes). NKO-Nes mice were born with Mendelian ratios but exhibited reduced growth characteristics compared to their littermates containing functional N-WASP alleles. Importantly, all NKO-Nes mice developed cranial deformities due to excessive CSF accumulation and did not survive past weaning. Coronal brain sections of these animals revealed dilated lateral ventricles, defects in ciliogenesis, loss of ependymal layer integrity, reduced thickness of cerebral cortex and aqueductal stenosis. Immunostaining for N-cadherin suggests that ependymal integrity in NKO-Nes mice is lost as compared to normal morphology in the wild-type controls. Moreover, scanning electron microscopy and immunofluorescence analyses of coronal brain sections with anti-acetylated tubulin antibodies revealed the absence of cilia in ventricular walls of NKO-Nes mice indicative of ciliogenesis defects. N-WASP deficiency does not lead to altered expression of N-WASP regulatory proteins, Fyn and Cdc42, which have been previously implicated in hydrocephalus pathology. Taken together, our results suggest that N-WASP plays a critical role in normal brain development and implicate actin cytoskeleton regulation as a vulnerable axis frequently deregulated in hydrocephalus.
    Experimental Neurology 01/2014; 254. DOI:10.1016/j.expneurol.2014.01.011 · 4.70 Impact Factor
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    • "Mice lacking both sperm associated antigens 6 (Spag6) and 16 L (Spag16L), which have been shown to interact in the cilium, have severe lower airway disease characterized by pneumonia, atelectases, and hemorrhage [34,35]. Despite the presence of other PCD phenotypes, respiratory abnormalities were not reported in mutants lacking either individual protein [36,37], possibly due to the functional relationship between the two proteins. Loss of Spag17 also results in PCD, with homozygous mutants exhibiting an accumulation of fluid in their lungs, damage to the alveolar cells, and a failure to thrive [38]. "
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    ABSTRACT: Lower airway abnormalities are common in patients with primary ciliary dyskinesia (PCD), a pediatric syndrome that results from structural or functional defects in motile cilia. Patients can suffer from recurrent bacterial infection in the lung, bronchiectasis, and respiratory distress in addition to chronic sinusitis, otitis media, infertility, and laterality defects. However, surprisingly little is known about the pulmonary phenotype of mouse models of this disorder. The pulmonary phenotype of two mouse models of PCD, nm1054 and bgh, which lack Pcdp1 and Spef2, respectively, was investigated by histological and immunohistochemical analysis. In addition, both models were challenged with Streptococcus pneumoniae, a common respiratory pathogen found in the lungs of PCD patients. Histopathological analyses reveal no detectable cellular, developmental, or inflammatory abnormalities in the lower airway of either PCD model. However, exposure to S. pneumoniae results in a markedly enhanced inflammatory response in both models. Based on analysis of inflammatory cells in bronchoalveolar lavage fluid and flow cytometric analysis of cytokines in the lung, the bgh model shows a particularly dramatic lymphocytic response by 3 days post-infection compared to the nm1054 model or wild type animals. Defects in ciliary motility result in a severe response to pulmonary infection. The PCD models nm1054 and bgh are distinct and clinically relevant models for future studies investigating the role of mucociliary clearance in host defense.
    Cilia 12/2013; 2(1):18. DOI:10.1186/2046-2530-2-18
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    • "Immotile cilia result in impaired CSF transport (ependymal flow) as well, as encountered in certain ciliopathies [4,5]. Ciliary immotility leading to hydrocephalus has been shown to result from mutations in structural proteins, such as Spag6 [6] or axonemal motor proteins such as Dnahc5. Mice deficient in Mdnah5[7] for example have no detectable ependymal flow, ultimately leading to stenosis of the cerebral aqueduct and hydrocephalus in the lateral and third ventricles [5,7]. "
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    ABSTRACT: Circulation of cerebrospinal fluid (CSF) through the ventricular system is driven by motile cilia on ependymal cells of the brain. Disturbed ciliary motility induces the formation of hydrocephalus, a pathological accumulation of CSF resulting in ventricle dilatation and increased intracranial pressure. The mechanism by which loss of motile cilia causes hydrocephalus has not been elucidated. The aim of this study was: (1) to provide a detailed account of the development of ciliation in the brain of the African clawed frog Xenopus laevis; and (2) to analyze the relevance of ependymal cilia motility for CSF circulation and brain ventricle morphogenesis in Xenopus. Gene expression analysis of foxj1, the bona fide marker for motile cilia, was used to identify potentially ciliated regions in the developing central nervous system (CNS) of the tadpole. Scanning electron microscopy (SEM) was used to reveal the distribution of mono- and multiciliated cells during successive stages of brain morphogenesis, which was functionally assessed by bead injection and video microscopy of ventricular CSF flow. An antisense morpholino oligonucleotide (MO)-mediated gene knock-down that targeted foxj1 in the CNS was applied to assess the role of motile cilia in the ventricles. RNA transcripts of foxj1 in the CNS were found from neurula stages onwards. Following neural tube closure, foxj1 expression was seen in distinct ventricular regions such as the zona limitans intrathalamica (ZLI), subcommissural organ (SCO), floor plate, choroid plexus (CP), and rhombomere boundaries. In all areas, expression of foxj1 preceded the outgrowth of monocilia and the subsequent switch to multiciliated ependymal cells. Cilia were absent in foxj1 morphants, causing impaired CSF flow and fourth ventricle hydrocephalus in tadpole-stage embryos. Motile ependymal cilia are important organelles in the Xenopus CNS, as they are essential for the circulation of CSF and maintenance of homeostatic fluid pressure. The Xenopus CNS ventricles might serve as a novel model system for the analysis of human ciliary genes whose deficiency cause hydrocephalus.
    Cilia 09/2013; 2(1):12. DOI:10.1186/2046-2530-2-12
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