title: Disruption of Ttll5/stamp gene (tubulin tyrosine ligase-like protein 5/SRC-1 and TIF2-associated modulatory protein gene) in male mice causes sperm malformation and infertility.
abstract: TTLL5/STAMP (tubulin tyrosine ligase-like family member 5) has multiple activities in cells. TTLL5 is one of 13 TTLLs, has polyglutamylation activity, augments the activity of p160 coactivators (SRC-1 and TIF2) in glucocorticoid receptor-regulated gene induction and repression, and displays steroid-independent growth activity with several cell types. To examine TTLL5/STAMP functions in whole animals, mice were prepared with an internal deletion that eliminated several activities of the Stamp gene. This mutation causes both reduced levels of STAMP mRNA and C-terminal truncation of STAMP protein. Homozygous targeted mutant (Stamp(tm/tm)) mice appear normal except for marked decreases in male fertility associated with defects in progressive sperm motility. Abnormal axonemal structures with loss of tubulin doublets occur in most Stamp(tm/tm) sperm tails in conjunction with substantial reduction in α-tubulin polyglutamylation, which closely correlates with the reduction in mutant STAMP mRNA. The axonemes in other structures appear unaffected. There is no obvious change in the organs for sperm development of WT versus Stamp(tm/tm) males despite the levels of WT STAMP mRNA in testes being 20-fold higher than in any other organ examined. This defect in male fertility is unrelated to other Ttll genes or 24 genes previously identified as important for sperm function. Thus, STAMP appears to participate in a unique, tissue-selective TTLL-mediated pathway for α-tubulin polyglutamylation that is required for sperm maturation and motility and may be relevant for male fertility.
authors.affiliation: Steroid Hormones Section, Laboratory of Endocrinology and Receptor Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1772, USA.
authors.forename: Geun-Shik
authors.initials: GS
authors.lastname: Lee
authors.forename: Yuanzheng
authors.initials: Y
authors.lastname: He
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Dougherty
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez-Movilla
authors.forename: Matteo
authors.initials: M
authors.lastname: Avella
authors.forename: Sean
authors.initials: S
authors.lastname: Grullon
authors.forename: David S
authors.initials: DS
authors.lastname: Sharlin
authors.forename: Chunhua
authors.initials: C
authors.lastname: Guo
authors.forename: John A
authors.initials: JA
authors.lastname: Blackford
authors.forename: Smita
authors.initials: S
authors.lastname: Awasthi
authors.forename: Zhenhuan
authors.initials: Z
authors.lastname: Zhang
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Armstrong
authors.forename: Edra C
authors.initials: EC
authors.lastname: London
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.forename: Jurrien
authors.initials: J
authors.lastname: Dean
authors.forename: S Stoney
authors.initials: SS
authors.lastname: Simons
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D007248:Infertility, Male / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D056920:Nuclear Receptor Coactivator 1 / Q000235:genetics / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2 / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D013081:Sperm Motility; D013094:Spermatozoa / Q000378:metabolism* / Q000473:pathology; D013737:Testis / Q000378:metabolism* / Q000473:pathology; D014404:Tubulin / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C498002:Ncoa2 protein, mouse; D051958:Nuclear Receptor Coactivator 2; D014404:Tubulin; C538861:Ncoa1 protein, mouse; D056920:Nuclear Receptor Coactivator 1
keywords: Disrupted Axoneme Formation; Fertilization; Gene Expression; Gene Hypomorph; Gene Knockout; Male Infertility; Spermatogenesis; Ttll5/Stamp Targeted Mutation Mice; Tubulin; α-Tubulin Polyglutamylation
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