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• W2973127939 abstract "Accumulated evidence shows that sperm-associated antigen 6 (SPAG6) gene has multiple biological functions. It maintains the normal function of a variety of cells including ciliary/flagellar biogenesis and polarization, neurogenesis, and neuronal migration. Moreover, SPAG6 is found to be critically involved in auditory transduction and the fibroblast life cycle. Furthermore, SPAG6 plays an essential role in immuno-regulation. Notably, SPAG6 has been demonstrated to participate in the occurrence and progression of a variety of human cancers. New evidence shows that SPAG6 gene regulates tumor cell proliferation, apoptosis, invasion, and metastasis. Therefore, in this review, we describe the physiological function and mechanism of SPAG6 in human normal cells and cancer cells. We also highlight that SPAG6 gene may be an effective biomarker for the diagnosis of human cancer. Taken together, targeting SPAG6 could be a novel strategy for the treatment of human diseases including cancer. Accumulated evidence shows that sperm-associated antigen 6 (SPAG6) gene has multiple biological functions. It maintains the normal function of a variety of cells including ciliary/flagellar biogenesis and polarization, neurogenesis, and neuronal migration. Moreover, SPAG6 is found to be critically involved in auditory transduction and the fibroblast life cycle. Furthermore, SPAG6 plays an essential role in immuno-regulation. Notably, SPAG6 has been demonstrated to participate in the occurrence and progression of a variety of human cancers. New evidence shows that SPAG6 gene regulates tumor cell proliferation, apoptosis, invasion, and metastasis. Therefore, in this review, we describe the physiological function and mechanism of SPAG6 in human normal cells and cancer cells. We also highlight that SPAG6 gene may be an effective biomarker for the diagnosis of human cancer. Taken together, targeting SPAG6 could be a novel strategy for the treatment of human diseases including cancer. The sperm-associated antigen 6 (SPAG6), also known as CT141, repro-sa-1, RP11-301N24.4, and pf16, was identified as a cancer-testis antigen (CTA) and is encoded by a gene located at chromosome 10p12.3.1Siliņa K. Zayakin P. Kalniņa Z. Ivanova L. Meistere I. Endzeliņš E. Abols A. Stengrēvics A. Leja M. Ducena K. et al.Sperm-associated antigens as targets for cancer immunotherapy: expression pattern and humoral immune response in cancer patients.J. Immunother. 2011; 34: 28-44Crossref PubMed Scopus (62) Google Scholar, 2Neilson L.I. Schneider P.A. Van Deerlin P.G. Kiriakidou M. Driscoll D.A. Pellegrini M.C. Millinder S. Yamamoto K.K. French C.K. Strauss 3rd, J.F. cDNA cloning and characterization of a human sperm antigen (SPAG6) with homology to the product of the Chlamydomonas PF16 locus.Genomics. 1999; 60: 272-280Crossref PubMed Scopus (62) Google Scholar Human SPAG6 has nine splicing variants: SPAG6-201, SPAG6-202, SPAG6-203, SPAG6-204, SPAG6-205, SPAG6-206, SPAG6-207, SPAG6-208, and SPAG6-209 (Figure 1). Murine SPAG6 also exists in the form of two isoforms, the parental SPAG6-BC061194 and its derivative, that are encoded by two homologous genes.3Qiu H. Gołas A. Grzmil P. Wojnowski L. Lineage-specific duplications of Muroidea Faim and Spag6 genes and atypical accelerated evolution of the parental Spag6 gene.J. Mol. Evol. 2013; 77: 119-129Crossref PubMed Scopus (10) Google Scholar The SPAG6 mRNA consists of 10 exons and 16 domains, whereas the protein contains eight consecutive WD repeats, which are known to mediate protein-protein interactions during brain development (Figure 1; Figure S1).4Zhang Z. Sapiro R. Kapfhamer D. Bucan M. Bray J. Chennathukuzhi V. McNamara P. Curtis A. Zhang M. Blanchette-Mackie E.J. Strauss 3rd, J.F. A sperm-associated WD repeat protein orthologous to Chlamydomonas PF20 associates with Spag6, the mammalian orthologue of Chlamydomonas PF16.Mol. Cell. Biol. 2002; 22: 7993-8004Crossref PubMed Scopus (70) Google Scholar Studies indicate that SPAG6 is a microtubule-associated protein that is essential for cytoskeleton formation. For instance, SPAG6 is present in the central organ protein of algae C1 microtubules and is a component of the central organ of the “9+2” axon,5Cooley L.F. El Shikh M.E. Li W. Keim R.C. Zhang Z. Strauss J.F. Zhang Z. Conrad D.H. Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice.Sci. Rep. 2016; 6: 25840Crossref PubMed Scopus (17) Google Scholar which is essential for ciliary and flagellar movement. In addition, it has also been detected in the inner ear hair cells, lung bronchial cells, ovarian epithelial cells, lymphocytes, and fibroblasts,6Teves M.E. Zhang Z. Costanzo R.M. Henderson S.C. Corwin F.D. Zweit J. Sundaresan G. Subler M. Salloum F.N. Rubin B.K. Strauss 3rd, J.F. Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival.Am. J. Respir. Cell Mol. Biol. 2013; 48: 765-772Crossref PubMed Scopus (37) Google Scholar, 7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar as well as in testicular germ cell tumors, hematological malignancies, breast and lung cancer, and bladder cancer.1Siliņa K. Zayakin P. Kalniņa Z. Ivanova L. Meistere I. Endzeliņš E. Abols A. Stengrēvics A. Leja M. Ducena K. et al.Sperm-associated antigens as targets for cancer immunotherapy: expression pattern and humoral immune response in cancer patients.J. Immunother. 2011; 34: 28-44Crossref PubMed Scopus (62) Google Scholar, 8An T. Gong Y. Li X. Kong L. Ma P. Gong L. Zhu H. Yu C. Liu J. Zhou H. et al.USP7 inhibitor P5091 inhibits Wnt signaling and colorectal tumor growth.Biochem. Pharmacol. 2017; 131: 29-39Crossref PubMed Scopus (76) Google Scholar, 9Steinbach D. Schramm A. Eggert A. Onda M. Dawczynski K. Rump A. Pastan I. Wittig S. Pfaffendorf N. Voigt A. et al.Identification of a set of seven genes for the monitoring of minimal residual disease in pediatric acute myeloid leukemia.Clin. Cancer Res. 2006; 12: 2434-2441Crossref PubMed Scopus (104) Google Scholar In this review, we focus on the function of SPAG6 in various cells and the molecular mechanism involved in SPAG6-mediated tumorigenesis and progression. In addition, we also discuss its potential role in tumor diagnosis and treatment. As a microtubule-binding protein, SPAG6 plays an important role in the biogenesis of motility structures like cilia and flagella,10Lee L. Campagna D.R. Pinkus J.L. Mulhern H. Wyatt T.A. Sisson J.H. Pavlik J.A. Pinkus G.S. Fleming M.D. Primary ciliary dyskinesia in mice lacking the novel ciliary protein Pcdp1.Mol. Cell. Biol. 2008; 28: 949-957Crossref PubMed Scopus (87) Google Scholar although the mechanisms are likely different.10Lee L. Campagna D.R. Pinkus J.L. Mulhern H. Wyatt T.A. Sisson J.H. Pavlik J.A. Pinkus G.S. Fleming M.D. Primary ciliary dyskinesia in mice lacking the novel ciliary protein Pcdp1.Mol. Cell. Biol. 2008; 28: 949-957Crossref PubMed Scopus (87) Google Scholar The motile cilia are formed after the assembly of nine microtubules with two linear centripetal microtubules,11Coutton C. Martinez G. Kherraf Z.E. Amiri-Yekta A. Boguenet M. Saut A. He X. Zhang F. Cristou-Kent M. Escoffier J. et al.Bi-allelic Mutations in ARMC2 Lead to Severe Astheno-Teratozoospermia Due to Sperm Flagellum Malformations in Humans and Mice.Am. J. Hum. Genet. 2019; 104: 331-340Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and spag6 knockout mice ciliary drift because of the loss of ciliary pair of central tubulin.12Sapiro R. Kostetskii I. Olds-Clarke P. Gerton G.L. Radice G.L. Strauss III, J.F. Male infertility, impaired sperm motility, and hydrocephalus in mice deficient in sperm-associated antigen 6.Mol. Cell. Biol. 2002; 22: 6298-6305Crossref PubMed Scopus (254) Google Scholar Zhang et al.13Zhang Z. Tang W. Zhou R. Shen X. Wei Z. Patel A.M. Povlishock J.T. Bennett J. Strauss 3rd, J.F. Accelerated mortality from hydrocephalus and pneumonia in mice with a combined deficiency of SPAG6 and SPAG16L reveals a functional interrelationship between the two central apparatus proteins.Cell Motil. Cytoskeleton. 2007; 64: 360-376Crossref PubMed Scopus (53) Google Scholar showed that spag6−/− mice had intact cilia on their trachea epithelial cells with the “9+2” axoneme structure, whereas another study found that the bronchial epithelial cell ciliary function was defective in these mice.7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar Furthermore, the spermatozoan flagella of the spag6−/− mice have the “9+1” or “9+0” axoneme arrangement.5Cooley L.F. El Shikh M.E. Li W. Keim R.C. Zhang Z. Strauss J.F. Zhang Z. Conrad D.H. Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice.Sci. Rep. 2016; 6: 25840Crossref PubMed Scopus (17) Google Scholar SPAG6 can affect the function of these motility structures by altering the apical microtubule network,7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar which lies upstream of the planar cell polarity (PCP) signaling cascade14Shimada Y. Yonemura S. Ohkura H. Strutt D. Uemura T. Polarized transport of Frizzled along the planar microtubule arrays in Drosophila wing epithelium.Dev. Cell. 2006; 10: 209-222Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar, 15Zheng J. Liu H. Zhu L. Chen Y. Zhao H. Zhang W. Li F. Xie L. Yan X. Zhu X. Microtubule-bundling protein Spef1 enables mammalian ciliary central apparatus formation.J. Mol. Cell Biol. 2019; 11: 67-77Crossref PubMed Scopus (23) Google Scholar and controls the tissue-level polarity of tracheal epithelial cells.16Mitchell B. Stubbs J.L. Huisman F. Taborek P. Yu C. Kintner C. The PCP pathway instructs the planar orientation of ciliated cells in the Xenopus larval skin.Curr. Biol. 2009; 19: 924-929Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar The PCP proteins Prickle2, Dishevelled1, Dvl2, Vangl1, and Vangl2 localize asymmetrically to the tracheal epithelial cell cortex,17Vladar E.K. Bayly R.D. Sangoram A.M. Scott M.P. Axelrod J.D. Microtubules enable the planar cell polarity of airway cilia.Curr. Biol. 2012; 22: 2203-2212Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar and disruption of these proteins obliterates rotational polarity of these cells.18Fischer D. Laiho A. Gyenesei A. Sironen A. Identification of Reproduction-Related Gene Polymorphisms Using Whole Transcriptome Sequencing in the Large White Pig Population.G3 (Bethesda). 2015; 5: 1351-1360Crossref PubMed Scopus (25) Google Scholar, 19Bogoyevitch M.A. Yeap Y.Y. Qu Z. Ngoei K.R. Yip Y.Y. Zhao T.T. Heng J.I. Ng D.C. WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.J. Cell Sci. 2012; 125: 5096-5109Crossref PubMed Scopus (60) Google Scholar, 20Tissir F. Qu Y. Montcouquiol M. Zhou L. Komatsu K. Shi D. Fujimori T. Labeau J. Tyteca D. Courtoy P. et al.Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus.Nat. Neurosci. 2010; 13: 700-707Crossref PubMed Scopus (254) Google Scholar The distribution of the PCP proteins is also disrupted in the spag6−/− mice, which impairs the sub-apical microtubule stability and polarization of basal bodies in the relevant cells.7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar Furthermore, Teves et al.6Teves M.E. Zhang Z. Costanzo R.M. Henderson S.C. Corwin F.D. Zweit J. Sundaresan G. Subler M. Salloum F.N. Rubin B.K. Strauss 3rd, J.F. Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival.Am. J. Respir. Cell Mol. Biol. 2013; 48: 765-772Crossref PubMed Scopus (37) Google Scholar detected arrhythmic and reduced ciliary beat in the tracheal epithelial cells of spag6−/− mice, along with disarrayed and significantly sparse cilia. In addition, the orientation of the basal feet that determine axoneme orientation was random,7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar and the levels of mucin, α-tubulin, and Vangl2 were significantly decreased.7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar Taken together, SPAG6 regulates ciliary/flagellar motility, and ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are adversely affected in its absence.7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar Studies have increasingly shown a critical role of SPAG6 in neurological functions.19Bogoyevitch M.A. Yeap Y.Y. Qu Z. Ngoei K.R. Yip Y.Y. Zhao T.T. Heng J.I. Ng D.C. WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.J. Cell Sci. 2012; 125: 5096-5109Crossref PubMed Scopus (60) Google Scholar Co-localization of SPAG6 and microtubules has been observed in various cells lines,4Zhang Z. Sapiro R. Kapfhamer D. Bucan M. Bray J. Chennathukuzhi V. McNamara P. Curtis A. Zhang M. Blanchette-Mackie E.J. Strauss 3rd, J.F. A sperm-associated WD repeat protein orthologous to Chlamydomonas PF20 associates with Spag6, the mammalian orthologue of Chlamydomonas PF16.Mol. Cell. Biol. 2002; 22: 7993-8004Crossref PubMed Scopus (70) Google Scholar, 21Kitchen M.O. Bryan R.T. Haworth K.E. Emes R.D. Luscombe C. Gommersall L. Cheng K.K. Zeegers M.P. James N.D. Devall A.J. et al.Methylation of HOXA9 and ISL1 Predicts Patient Outcome in High-Grade Non-Invasive Bladder Cancer.PLoS ONE. 2015; 10: e0137003Crossref PubMed Scopus (33) Google Scholar, 22Lonergan K.M. Chari R. Deleeuw R.J. Shadeo A. Chi B. Tsao M.S. Jones S. Marra M. Ling V. Ng R. et al.Identification of novel lung genes in bronchial epithelium by serial analysis of gene expression.Am. J. Respir. Cell Mol. Biol. 2006; 35: 651-661Crossref PubMed Scopus (47) Google Scholar and SPAG6 is overexpressed in the chicken embryonic spinal cord.23Hamada T. Teraoka M. Imaki J. Ui-Tei K. Ladher R.K. Asahara T. Gene expression of Spag6 in chick central nervous system.Anat. Histol. Embryol. 2010; 39: 227-232Crossref PubMed Scopus (12) Google Scholar The human SPAG6 and the Chlamydomonas pf16 can bind to the centrosome proteins Wdr62 and LIS1 through their contiguous WD repeats,24Hu X. Yan R. Cheng X. Song L. Zhang W. Li K. Zhao S. The function of sperm-associated antigen 6 in neuronal proliferation and differentiation.J. Mol. Histol. 2016; 47: 531-540Crossref PubMed Scopus (15) Google Scholar, 25Mulaw M.A. Krause A. Deshpande A.J. Krause L.F. Rouhi A. La Starza R. Borkhardt A. Buske C. Mecucci C. Ludwig W.D. et al.CALM/AF10-positive leukemias show upregulation of genes involved in chromatin assembly and DNA repair processes and of genes adjacent to the breakpoint at 10p12.Leukemia. 2012; 26: 1012-1019Crossref PubMed Scopus (34) Google Scholar indicating their involvement in Wdr62-mediated mitotic spindle regulation and neurogenesis.19Bogoyevitch M.A. Yeap Y.Y. Qu Z. Ngoei K.R. Yip Y.Y. Zhao T.T. Heng J.I. Ng D.C. WD40-repeat protein 62 is a JNK-phosphorylated spindle pole protein required for spindle maintenance and timely mitotic progression.J. Cell Sci. 2012; 125: 5096-5109Crossref PubMed Scopus (60) Google Scholar Mitchell et al.16Mitchell B. Stubbs J.L. Huisman F. Taborek P. Yu C. Kintner C. The PCP pathway instructs the planar orientation of ciliated cells in the Xenopus larval skin.Curr. Biol. 2009; 19: 924-929Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar proposed that SPAG6 likely affects neuronal migration by targeting microtubules, which control centrosome movement and soma during neuronal migration,26Fulda S. Debatin K.M. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy.Oncogene. 2006; 25: 4798-4811Crossref PubMed Scopus (1738) Google Scholar, 27Wu Q. Liu J. Fang A. Li R. Bai Y. Kriegstein A.R. Wang X. The dynamics of neuronal migration.in: Cellular and Molecular Control of Neuronal Migration. Vol. 800. Springer, 2014: 25-36Crossref Google Scholar indicating that SPAG6 also plays a role in neural development.28Yan R. Hu X. Zhang Q. Song L. Zhang M. Zhang Y. Zhao S. Spag6 negatively regulates neuronal migration during mouse brain development.J. Mol. Neurosci. 2015; 57: 463-469Crossref PubMed Scopus (11) Google Scholar The two modes of neuronal migration, known as soma translocation and radial glia-dependent locomotion, need coordinated cytoskeletal remodeling.29Zeng W. Dai H. Yan M. Cai X. Luo H. Ke M. Liu Z. Decitabine-Induced Changes in Human Myelodysplastic Syndrome Cell Line SKM-1 Are Mediated by FOXO3A Activation.J. Immunol. Res. 2017; 2017: 4302320Crossref PubMed Scopus (15) Google Scholar Yan et al.28Yan R. Hu X. Zhang Q. Song L. Zhang M. Zhang Y. Zhao S. Spag6 negatively regulates neuronal migration during mouse brain development.J. Mol. Neurosci. 2015; 57: 463-469Crossref PubMed Scopus (11) Google Scholar showed that overexpression of SPAG6 delayed the rate of neuronal migration, branching, and elongation, indicating that it can stabilize the microtubules and prevent remodeling.28Yan R. Hu X. Zhang Q. Song L. Zhang M. Zhang Y. Zhao S. Spag6 negatively regulates neuronal migration during mouse brain development.J. Mol. Neurosci. 2015; 57: 463-469Crossref PubMed Scopus (11) Google Scholar Another study found fewer microtubules and actin filaments, in addition to other abnormal membranous structures, in the spiral ganglion neurons (SGNs) of spag6−/− mice.30Li X. Xu L. Sun G. Wu X. Bai X. Li J. Strauss J.F. Zhang Z. Wang H. Spag6 Mutant Mice Have Defects in Development and Function of Spiral Ganglion Neurons, Apoptosis, and Higher Sensitivity to Paclitaxel.Sci. Rep. 2017; 7: 8638Crossref PubMed Scopus (15) Google Scholar SPAG6 is localized in the peri-nuclear cytoplasm of wild-type SGNs and decreased in the spag6−/− mice by perinatal day 30.30Li X. Xu L. Sun G. Wu X. Bai X. Li J. Strauss J.F. Zhang Z. Wang H. Spag6 Mutant Mice Have Defects in Development and Function of Spiral Ganglion Neurons, Apoptosis, and Higher Sensitivity to Paclitaxel.Sci. Rep. 2017; 7: 8638Crossref PubMed Scopus (15) Google Scholar Furthermore, RNAi-mediated inhibition of spag6 in multi-ciliated mouse ependymal cells completely abolished the central pair microtubules and ciliary localization of SPAG6, resulting in rotational ciliary movement.15Zheng J. Liu H. Zhu L. Chen Y. Zhao H. Zhang W. Li F. Xie L. Yan X. Zhu X. Microtubule-bundling protein Spef1 enables mammalian ciliary central apparatus formation.J. Mol. Cell Biol. 2019; 11: 67-77Crossref PubMed Scopus (23) Google Scholar Finally, the spag6 promoter is hypermethylated during the differentiation of human embryonic stem cells into neural progenitor/stem cells (NPCs) in vitro, indicating that SPAG6 levels are modulated during neurogenesis.31Shen Y. Chow J. Wang Z. Fan G. Abnormal CpG island methylation occurs during in vitro differentiation of human embryonic stem cells.Hum. Mol. Genet. 2006; 15: 2623-2635Crossref PubMed Scopus (67) Google Scholar SPAG6 is also essential for the mechano-sensory function of the cylindrical outer hair cells (OHCs) in the organ of Corti, which is the receptor organ for hearing in the mammalian cochlea.32Schwander M. Kachar B. Müller U. Review series: The cell biology of hearing.J. Cell Biol. 2010; 190: 9-20Crossref PubMed Scopus (213) Google Scholar Evidence suggests that patients with primary ciliated hair cells of Corti often have hearing impairment simultaneously.33Janke C. Bulinski J.C. Post-translational regulation of the microtubule cytoskeleton: mechanisms and functions.Nat. Rev. Mol. Cell Biol. 2011; 12: 773-786Crossref PubMed Scopus (619) Google Scholar The normal physiological function of the hair cells on the Corti is to maintain hearing production by changing their length and stiffness by a recognized molecular click that drives from a putative molecular motor designated prestin,34Zheng J. Shen W. He D.Z.Z. Long K.B. Madison L.D. Dallos P. Prestin is the motor protein of cochlear outer hair cells.Nature. 2000; 405: 149-155Crossref PubMed Scopus (991) Google Scholar, 35Yu N. Zhu M.L. Zhao H.B. Prestin is expressed on the whole outer hair cell basolateral surface.Brain Res. 2006; 1095: 51-58Crossref PubMed Scopus (48) Google Scholar and dyskinesia happens to the cilia of the hair cells missing spag6.36Gross J. Stute K. Fuchs J. Angerstein M. Amarjargal N. Mazurek B. Effects of retinoic acid and butyric acid on the expression of prestin and Gata-3 in organotypic cultures of the organ of corti of newborn rats.Dev. Neurobiol. 2011; 71: 650-661Crossref PubMed Scopus (8) Google Scholar Wang et al.37Wang J. Li X. Zhang Z. Wang H. Li J. Expression of prestin in OHCs is reduced in Spag6 gene knockout mice.Neurosci. Lett. 2015; 592: 42-47Crossref PubMed Scopus (10) Google Scholar were the first to detect SPAG6 in the OHCs, and they found that SPAG6 and the microtubule-associated protein MAP1S bound to and stabilized prestin,38Bai J.P. Surguchev A. Ogando Y. Song L. Bian S. Santos-Sacchi J. Navaratnam D. Prestin surface expression and activity are augmented by interaction with MAP1S, a microtubule-associated protein.J. Biol. Chem. 2010; 285: 20834-20843Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar which is essential for maintaining the normal function of the OHCs.37Wang J. Li X. Zhang Z. Wang H. Li J. Expression of prestin in OHCs is reduced in Spag6 gene knockout mice.Neurosci. Lett. 2015; 592: 42-47Crossref PubMed Scopus (10) Google Scholar In their study, immunofluorescent staining of SPAG6 and prestin shows expression of SPAG6 in the lateral wall of OHCs, and in the cuticular plate in OHCs, while prestin located in the cuticular plate of OHCs.37Wang J. Li X. Zhang Z. Wang H. Li J. Expression of prestin in OHCs is reduced in Spag6 gene knockout mice.Neurosci. Lett. 2015; 592: 42-47Crossref PubMed Scopus (10) Google Scholar Prestin protein and mRNA levels were decreased in SPAG6 defect mice.37Wang J. Li X. Zhang Z. Wang H. Li J. Expression of prestin in OHCs is reduced in Spag6 gene knockout mice.Neurosci. Lett. 2015; 592: 42-47Crossref PubMed Scopus (10) Google Scholar Li et al.39Li X. Xu L. Li J. Li B. Bai X. Strauss 3rd, J.F. Zhang Z. Wang H. Otitis media in sperm-associated antigen 6 (Spag6)-deficient mice.PLoS ONE. 2014; 9: e112879Crossref PubMed Scopus (22) Google Scholar studied the relationship between SPAG6 and otitis media, and they have proved that SPAG6 regulates cilia/basal body polarity through the PCP-dependent mechanisms that not only regulate cilium location or orientation, but also regulate basal body docking to the apical surface during ciliogenesis in the middle ear and Eustachian tubes.40Park T.J. Mitchell B.J. Abitua P.B. Kintner C. Wallingford J.B. Dishevelled controls apical docking and planar polarization of basal bodies in ciliated epithelial cells.Nat. Genet. 2008; 40: 871-879Crossref PubMed Scopus (355) Google Scholar, 41Bayly R. Axelrod J.D. Pointing in the right direction: new developments in the field of planar cell polarity.Nat. Rev. Genet. 2011; 12: 385-391Crossref PubMed Scopus (96) Google Scholar Li et al.’s39Li X. Xu L. Li J. Li B. Bai X. Strauss 3rd, J.F. Zhang Z. Wang H. Otitis media in sperm-associated antigen 6 (Spag6)-deficient mice.PLoS ONE. 2014; 9: e112879Crossref PubMed Scopus (22) Google Scholar study showed that the orientation of the ciliary basal feet was random in the middle ear epithelial cells of SPAG6-deficient mice. Frizzled class receptor 6 (FZD6), a core planar cell polarity (PCP) protein, is a mediator of the Wnt pathway and plays a critical role in differentiation and organism development.42Corda G. Sala A. Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage.Oncogenesis. 2017; 6: e364Crossref PubMed Scopus (62) Google Scholar FZD6 does not have a polarized distribution in the mutant tympanic ciliary epithelium,39Li X. Xu L. Li J. Li B. Bai X. Strauss 3rd, J.F. Zhang Z. Wang H. Otitis media in sperm-associated antigen 6 (Spag6)-deficient mice.PLoS ONE. 2014; 9: e112879Crossref PubMed Scopus (22) Google Scholar indicating that FZD6 protein location was altered by inactivation of SPAG6 in the middle ear, and that planar polarity of the middle ear was affected,39Li X. Xu L. Li J. Li B. Bai X. Strauss 3rd, J.F. Zhang Z. Wang H. Otitis media in sperm-associated antigen 6 (Spag6)-deficient mice.PLoS ONE. 2014; 9: e112879Crossref PubMed Scopus (22) Google Scholar which is in keeping with the report that FZD6 knockout mice have developmental disorders in the planar polarity of the OHC and neural tube closure,43Wang Y. Guo N. Nathans J. The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells.J. Neurosci. 2006; 26: 2147-2156Crossref PubMed Scopus (416) Google Scholar and “9+2” axonemes of cilia were conserved; also, the orientation of central microtubules was not uniform,39Li X. Xu L. Li J. Li B. Bai X. Strauss 3rd, J.F. Zhang Z. Wang H. Otitis media in sperm-associated antigen 6 (Spag6)-deficient mice.PLoS ONE. 2014; 9: e112879Crossref PubMed Scopus (22) Google Scholar indicating that as in the brain and lungs, SPAG6 mutation affects the polarity of the middle ear epithelium, with the gross structure of the “9+2” axonemes being conserved.7Li W. Mukherjee A. Wu J. Zhang L. Teves M.E. Li H. Nambiar S. Henderson S.C. Horwitz A.R. Strauss III, J.F. et al.Sperm Associated Antigen 6 (SPAG6) Regulates Fibroblast Cell Growth, Morphology, Migration and Ciliogenesis.Sci. Rep. 2015; 5: 16506Crossref PubMed Scopus (23) Google Scholar, 13Zhang Z. Tang W. Zhou R. Shen X. Wei Z. Patel A.M. Povlishock J.T. Bennett J. Strauss 3rd, J.F. Accelerated mortality from hydrocephalus and pneumonia in mice with a combined deficiency of SPAG6 and SPAG16L reveals a functional interrelationship between the two central apparatus proteins.Cell Motil. Cytoskeleton. 2007; 64: 360-376Crossref PubMed Scopus (53) Google Scholar It is interesting to note that other research has shown that the SPAG6 gene has not been associated with hair cell differentiation.44Yoon H. Lee D.J. Kim M.H. Bok J. Identification of genes concordantly expressed with Atoh1 during inner ear development.Anat. Cell Biol. 2011; 44: 69-78Crossref PubMed Google Scholar There are also some experimental observations worth exploring. In one study, the researchers found that SPAG6-deficient mice exhibited abnormal behaviors, such as logy motion and continuous head tossing, and fur loss occurred in comparison with their corresponding SPAG6 overexpression and SPAG6 normal expression littermates.37Wang J. Li X. Zhang Z. Wang H. Li J. Expression of prestin in OHCs is reduced in Spag6 gene knockout mice.Neurosci. Lett. 2015; 592: 42-47Crossref PubMed Scopus (10) Google Scholar The immune synapse has the same centrosome nucleation mechanism as the cilia and, therefore, similar functions.5Cooley L.F. El Shikh M.E. Li W. Keim R.C. Zhang Z. Strauss J.F. Zhang Z. Conrad D.H. Impaired immunological synapse in sperm associated antigen 6 (SPAG6) deficient mice.Sci. Rep. 2016; 6: 25840Crossref PubMed Scopus (17) Google Scholar Intraflagellar transport protein 20 (IFT20), a protein involved in ciliary formation like SPAG6, also plays an important role in the immune synapse between the T cell receptor (TCR) and antigen-presenting cells (APCs) or target cells.45Finetti F. Patrussi L. Masi G. Onnis A. Galgano D. Lucherini O.M. Pazour G.J. Baldari C.T. Specific recycling receptors are targeted to the immune synapse by the intraflagellar transport system.J. Cell Sci. 2014; 127: 1924-1937Crossref PubMed Scopus (77) Google Scholar, 46Stinchcombe J. Bossi G. Griffiths G.M. Linking albinism and immunity: the secrets of secretory lysosomes.Science. 2004; 305: 55-59Crossref PubMed Scopus (306) Google Scholar This led to the speculation that SPAG6 may also be involved in the lymphatic system. de la Roche et al.47de la Roche M. Ritter A.T. Angus K.L. Dinsmore C. Earnshaw C.H. Reiter J.F. Griffiths G.M. Hedgehog signaling controls T cell killing at the immunological synapse.Science. 2013; 342: 1247-1250Crossref PubMed Scopus (94) Google Scholar showed that the TCR immune synapses function as cilia at the junction of T cells and APCs/target cells. In addition, SPAG6 is expressed in both primary and secondary lymphoid tissues, and its deletion ruptured immune synapses because of the absence of centrosome polarization and actin clearance in the" @default.
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• W2973127939 date "2019-12-01" @default.
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• W2973127939 title "The Emerging Role of Sperm-Associated Antigen 6 Gene in the Microtubule Function of Cells and Cancer" @default.
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• W2973127939 doi "https://doi.org/10.1016/j.omto.2019.08.011" @default.
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