Article

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

Department of Anatomy and Cell Biology, Temple University, Filadelfia, Pennsylvania, United States
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

ABSTRACT

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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    • "ENSMUST00000164539 ENSMUST00000127518 ENSMUST00000152586 ENSMUST00000143050 Yes Non-coding Non-coding Non-coding 2320 - -Sapiro et al., 2000Sapiro et al., 2002Teves et al.,2014 "
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    ABSTRACT: Cilia and flagella are specialized organelles. The axoneme genes, their encoded proteins, their functions and the structures they form are believed to be conserved across species. Much of our knowledge of the function and structure of axoneme proteins in cilia and flagella is derived from studies on model organisms like the green algae, Chlamydomonas reinhardtii. The core structure of cilia and flagella is the axoneme, which in most motile cilia and flagella contains a 9 + 2 configuration of microtubules. The two central microtubules are the scaffold of the central pair complex (CPC). Mutations that disrupt CPC genes in Chlamydomonas and other model organisms result in defects in assembly, stability and function of the axoneme, leading to flagellar motility defects. However, targeted mutations generated in mice in the orthologous CPC genes have revealed significant differences in phenotypes of mutants compared to Chlamydomonas. Here we review observations that support the concept of cell-type specific roles for the CPC genes in mice, and an expanded repertoire of functions for the products of these genes in cilia, including non-motile cilia, and other microtubule-associated cellular functions. This article is protected by copyright. All rights reserved.
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    • "As a result, most models rely on genetic manipulation. Some studies utilize mutant animals lacking either cilia (Banizs et al., 2005; Chen et al., 1998; Sapiro et al., 2002) or have cilia with reduced motility (Ibanez-Tallon et al., 2004; Torikata et al., 1991). A study evaluating Tg737Orpk mice, which have a hypomorphic allele of Polaris that is an essential protein for ciliogenesis, showed that ciliary movement not only helps maintain CSF flow, but also directs tangential migration of neuroblasts born in the SVZ toward the olfactory bulb in mice with congenital hydrocephalus (Sawamoto et al., 2006). "
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    Full-text · Dataset · Dec 2015
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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.
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