Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival
Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infe...
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Veröffentlicht in: | American journal of respiratory cell and molecular biology 2013-06, Vol.48 (6), p.765-772 |
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creator | Teves, Maria Eugenia Zhang, Zhibing Costanzo, Richard M Henderson, Scott C Corwin, Frank D Zweit, Jamal Sundaresan, Gobalakrishnan Subler, Mark Salloum, Fadi N Rubin, Bruce K Strauss, 3rd, Jerome F |
description | Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance. |
doi_str_mv | 10.1165/rcmb.2012-0362OC |
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PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.</description><identifier>ISSN: 1044-1549</identifier><identifier>EISSN: 1535-4989</identifier><identifier>DOI: 10.1165/rcmb.2012-0362OC</identifier><identifier>PMID: 23418344</identifier><language>eng</language><publisher>United States: American Thoracic Society</publisher><subject>Amino Acid Sequence ; Animals ; Animals, Newborn ; Axoneme - metabolism ; Axoneme - ultrastructure ; Cell Movement ; Cilia - metabolism ; Cilia - ultrastructure ; Female ; Kartagener Syndrome - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microscopy, Electron, Transmission ; Microtubule Proteins - genetics ; Microtubule Proteins - metabolism ; Mutation ; Nasal Mucosa - metabolism ; Phenotype ; Survival Analysis ; Time Factors ; Trachea - anatomy & histology ; Trachea - metabolism ; Trachea - pathology</subject><ispartof>American journal of respiratory cell and molecular biology, 2013-06, Vol.48 (6), p.765-772</ispartof><rights>Copyright American Thoracic Society Jun 2013</rights><rights>Copyright © 2013 by the American Thoracic Society 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-c32a0d495cc2fc413bdd538ed477690c36983e34c7cc81858c1a96f9cb1c2edf3</citedby><cites>FETCH-LOGICAL-c424t-c32a0d495cc2fc413bdd538ed477690c36983e34c7cc81858c1a96f9cb1c2edf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23418344$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Teves, Maria Eugenia</creatorcontrib><creatorcontrib>Zhang, Zhibing</creatorcontrib><creatorcontrib>Costanzo, Richard M</creatorcontrib><creatorcontrib>Henderson, Scott C</creatorcontrib><creatorcontrib>Corwin, Frank D</creatorcontrib><creatorcontrib>Zweit, Jamal</creatorcontrib><creatorcontrib>Sundaresan, Gobalakrishnan</creatorcontrib><creatorcontrib>Subler, Mark</creatorcontrib><creatorcontrib>Salloum, Fadi N</creatorcontrib><creatorcontrib>Rubin, Bruce K</creatorcontrib><creatorcontrib>Strauss, 3rd, Jerome F</creatorcontrib><title>Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival</title><title>American journal of respiratory cell and molecular biology</title><addtitle>Am J Respir Cell Mol Biol</addtitle><description>Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.</description><subject>Amino Acid Sequence</subject><subject>Animals</subject><subject>Animals, Newborn</subject><subject>Axoneme - metabolism</subject><subject>Axoneme - ultrastructure</subject><subject>Cell Movement</subject><subject>Cilia - metabolism</subject><subject>Cilia - ultrastructure</subject><subject>Female</subject><subject>Kartagener Syndrome - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Microscopy, Electron, Transmission</subject><subject>Microtubule Proteins - genetics</subject><subject>Microtubule Proteins - metabolism</subject><subject>Mutation</subject><subject>Nasal Mucosa - metabolism</subject><subject>Phenotype</subject><subject>Survival Analysis</subject><subject>Time Factors</subject><subject>Trachea - 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metabolism</topic><topic>Axoneme - ultrastructure</topic><topic>Cell Movement</topic><topic>Cilia - metabolism</topic><topic>Cilia - ultrastructure</topic><topic>Female</topic><topic>Kartagener Syndrome - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Microscopy, Electron, Transmission</topic><topic>Microtubule Proteins - genetics</topic><topic>Microtubule Proteins - metabolism</topic><topic>Mutation</topic><topic>Nasal Mucosa - metabolism</topic><topic>Phenotype</topic><topic>Survival Analysis</topic><topic>Time Factors</topic><topic>Trachea - anatomy & histology</topic><topic>Trachea - metabolism</topic><topic>Trachea - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Teves, Maria Eugenia</creatorcontrib><creatorcontrib>Zhang, Zhibing</creatorcontrib><creatorcontrib>Costanzo, Richard M</creatorcontrib><creatorcontrib>Henderson, Scott C</creatorcontrib><creatorcontrib>Corwin, Frank D</creatorcontrib><creatorcontrib>Zweit, Jamal</creatorcontrib><creatorcontrib>Sundaresan, Gobalakrishnan</creatorcontrib><creatorcontrib>Subler, Mark</creatorcontrib><creatorcontrib>Salloum, Fadi N</creatorcontrib><creatorcontrib>Rubin, Bruce K</creatorcontrib><creatorcontrib>Strauss, 3rd, Jerome F</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of respiratory cell and molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Teves, Maria Eugenia</au><au>Zhang, Zhibing</au><au>Costanzo, Richard M</au><au>Henderson, Scott C</au><au>Corwin, Frank D</au><au>Zweit, Jamal</au><au>Sundaresan, Gobalakrishnan</au><au>Subler, Mark</au><au>Salloum, Fadi N</au><au>Rubin, Bruce K</au><au>Strauss, 3rd, Jerome F</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival</atitle><jtitle>American journal of respiratory cell and molecular biology</jtitle><addtitle>Am J Respir Cell Mol Biol</addtitle><date>2013-06</date><risdate>2013</risdate><volume>48</volume><issue>6</issue><spage>765</spage><epage>772</epage><pages>765-772</pages><issn>1044-1549</issn><eissn>1535-4989</eissn><abstract>Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.</abstract><cop>United States</cop><pub>American Thoracic Society</pub><pmid>23418344</pmid><doi>10.1165/rcmb.2012-0362OC</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amino Acid Sequence Animals Animals, Newborn Axoneme - metabolism Axoneme - ultrastructure Cell Movement Cilia - metabolism Cilia - ultrastructure Female Kartagener Syndrome - pathology Male Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Electron, Transmission Microtubule Proteins - genetics Microtubule Proteins - metabolism Mutation Nasal Mucosa - metabolism Phenotype Survival Analysis Time Factors Trachea - anatomy & histology Trachea - metabolism Trachea - pathology |
title | Sperm-associated antigen-17 gene is essential for motile cilia function and neonatal survival |
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