Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice
Autoři:
Ya-Yun Wang aff001; Chih-Chun Ke aff002; Yen-Lin Chen aff004; Yu-Hua Lin aff006; I-Shing Yu aff008; Wei-Chi Ku aff005; Moira K. O’Bryan aff009; Ying-Hung Lin aff001
Působiště autorů:
Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, New Taipei City, Taiwan
aff001; PhD Program in Nutrition & Food science, Fu Jen Catholic University, New Taipei City, Taiwan
aff002; Department of Urology, En Chu Kong Hospital, New Taipei City, Taiwan
aff003; Department of Pathology, Cardinal Tien Hospital, New Taipei City, Taiwan
aff004; School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
aff005; Division of Urology, Department of Surgery, Cardinal Tien Hospital, New Taipei City, Taiwan
aff006; Department of Chemistry, Fu Jen Catholic University, New Taipei City, Taiwan
aff007; Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan
aff008; School of Biological Sciences, Monash University, Melbourne, Victoria, Australia
aff009
Vyšlo v časopise:
Deficiency of the Tbc1d21 gene causes male infertility with morphological abnormalities of the sperm mitochondria and flagellum in mice. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1009020
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009020
Souhrn
Approximately 2–15% of couples experience infertility, and around half of these cases are attributed to male infertility. We previously identified TBC1D21 as a sterility-related RabGAP gene derived from infertile men. However, the in vivo function of TBC1D21 in male fertility remains unclear. Here, we show that loss of Tbc1d21 in mice resulted in male infertility, characterized by defects in sperm tail structure and diminished sperm motility. The mitochondria of the sperm-tail had an abnormal irregular arrangement, abnormal diameter, and structural defects. Moreover, the axoneme structure of sperm tails was severely disturbed. Several TBC1D21 interactors were selected via proteomic analysis and functional grouping. Two of the candidate interactors, a subunit protein of translocase in the outer membrane of mitochondria (TOMM20) and an inner arm component of the sperm tail axoneme (Dynein Heavy chain 7, DNAH7), confirmed in vivo physical co-localization with TBC1D21. In addition, TOMM20 and DNAH7 detached and dispersed outside the axoneme in Tbc1d21-deficient sperm, instead of aligning with the axoneme. From a clinical perspective, the transcript levels of TBC1D21 in sperm from teratozoospermia cases were significantly reduced when compared with those in normozoospermia. We concluded that TBC1D21 is critical for mitochondrial and axoneme development of mammalian sperm.
Klíčová slova:
Epididymis – Genetically modified animals – Male infertility – Mitochondria – Mouse models – Outer membrane proteins – Sperm – Tails
Zdroje
1. Ostermeier GC, Dix DJ, Miller D, Khatri P, Krawetz SA (2002) Spermatozoal RNA profiles of normal fertile men. Lancet 360: 772–777. doi: 10.1016/S0140-6736(02)09899-9 12241836
2. Ji G, Long Y, Zhou Y, Huang C, Gu A, et al. (2012) Common variants in mismatch repair genes associated with increased risk of sperm DNA damage and male infertility. BMC Med 10: 49. doi: 10.1186/1741-7015-10-49 22594646
3. Matzuk MM, Lamb DJ (2008) The biology of infertility: research advances and clinical challenges. Nat Med 14: 1197–1213. doi: 10.1038/nm.f.1895 18989307
4. Krausz C, Degl'Innocenti S, Nuti F, Morelli A, Felici F, et al. (2006) Natural transmission of USP9Y gene mutations: a new perspective on the role of AZFa genes in male fertility. Hum Mol Genet 15: 2673–2681. doi: 10.1093/hmg/ddl198 16893908
5. Houston BJ, Conrad DF, O'Bryan MK (2020) A framework for high-resolution phenotyping of candidate male infertility mutants: from human to mouse. Hum Genet.
6. Okabe M, Ikawa M, Ashkenas J (1998) Male infertility and the genetics of spermatogenesis. Am J Hum Genet 62: 1274–1281. doi: 10.1086/301895 9644029
7. Bracke A, Peeters K, Punjabi U, Hoogewijs D, Dewilde S (2018) A search for molecular mechanisms underlying male idiopathic infertility. Reprod Biomed Online 36: 327–339. doi: 10.1016/j.rbmo.2017.12.005 29336995
8. Frasa MA, Maximiano FC, Smolarczyk K, Francis RE, Betson ME, et al. (2010) Armus is a Rac1 effector that inactivates Rab7 and regulates E-cadherin degradation. Curr Biol 20: 198–208. doi: 10.1016/j.cub.2009.12.053 20116244
9. Falace A, Filipello F, La Padula V, Vanni N, Madia F, et al. (2010) TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet 87: 365–370. doi: 10.1016/j.ajhg.2010.07.020 20727515
10. Lonnie DR RA (1990) Histological and Histopathological Evaluation of the Testis Cache River Press.
11. Dunleavy JEM, O'Bryan M, Stanton PG, O'Donnell L (2018) The Cytoskeleton in Spermatogenesis. Reproduction.
12. Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81: 153–208. doi: 10.1152/physrev.2001.81.1.153 11152757
13. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129: 865–877. doi: 10.1016/j.cell.2007.05.018 17540168
14. Pan X, Eathiraj S, Munson M, Lambright DG (2006) TBC-domain GAPs for Rab GTPases accelerate GTP hydrolysis by a dual-finger mechanism. Nature 442: 303–306. doi: 10.1038/nature04847 16855591
15. Csepanyi-Komi R, Levay M, Ligeti E (2012) Small G proteins and their regulators in cellular signalling. Mol Cell Endocrinol 353: 10–20. doi: 10.1016/j.mce.2011.11.005 22108439
16. Richardson PM, Zon LI (1995) Molecular cloning of a cDNA with a novel domain present in the tre-2 oncogene and the yeast cell cycle regulators BUB2 and cdc16. Oncogene 11: 1139–1148. 7566974
17. Segev N (2001) Ypt and Rab GTPases: insight into functions through novel interactions. Curr Opin Cell Biol 13: 500–511. doi: 10.1016/s0955-0674(00)00242-8 11454458
18. Fukuda M (2011) TBC proteins: GAPs for mammalian small GTPase Rab? Biosci Rep 31: 159–168. doi: 10.1042/BSR20100112 21250943
19. Iida H, Yoshinaga Y, Tanaka S, Toshimori K, Mori T (1999) Identification of Rab3A GTPase as an acrosome-associated small GTP-binding protein in rat sperm. Dev Biol 211: 144–155. doi: 10.1006/dbio.1999.9302 10373312
20. Kierszenbaum AL, Tres LL (2004) The acrosome-acroplaxome-manchette complex and the shaping of the spermatid head. Arch Histol Cytol 67: 271–284. doi: 10.1679/aohc.67.271 15700535
21. Lau AS, Mruk DD (2003) Rab8B GTPase and junction dynamics in the testis. Endocrinology 144: 1549–1563. doi: 10.1210/en.2002-220893 12639940
22. Lui WY, Mruk DD, Cheng CY (2005) Interactions among IQGAP1, Cdc42, and the cadherin/catenin protein complex regulate Sertoli-germ cell adherens junction dynamics in the testis. J Cell Physiol 202: 49–66. doi: 10.1002/jcp.20098 15389538
23. Mountjoy JR, Xu W, McLeod D, Hyndman D, Oko R (2008) RAB2A: a major subacrosomal protein of bovine spermatozoa implicated in acrosomal biogenesis. Biol Reprod 79: 223–232. doi: 10.1095/biolreprod.107.065060 18401013
24. Ramalho-Santos J, Moreno RD (2001) Targeting and fusion proteins during mammalian spermiogenesis. Biol Res 34: 147–152. doi: 10.4067/s0716-97602001000200021 11715208
25. Berruti G (2003) CAMP activates Rap1 in differentiating mouse male germ cells: a new signaling pathway mediated by the cAMP-activated exchange factor Epac? Cell Mol Biol (Noisy-le-grand) 49: 381–388.
26. Duchniewicz M, Zemojtel T, Kolanczyk M, Grossmann S, Scheele JS, et al. (2006) Rap1A-deficient T and B cells show impaired integrin-mediated cell adhesion. Mol Cell Biol 26: 643–653. doi: 10.1128/MCB.26.2.643-653.2006 16382154
27. Berruti G, Paiardi C (2014) The dynamic of the apical ectoplasmic specialization between spermatids and Sertoli cells: the case of the small GTPase Rap1. Biomed Res Int 2014: 635979. doi: 10.1155/2014/635979 24719879
28. Yang B, Sun H, Li W, Zhu C, Jian B, et al. (2013) Expression of Rap1 during germ cell development in the rat and its functional implications in 2-methoxyacetic acid-induced spermatocyte apoptosis. Urology 81: 696 e691–698.
29. Lo JC, Jamsai D, O'Connor AE, Borg C, Clark BJ, et al. (2012) RAB-like 2 has an essential role in male fertility, sperm intra-flagellar transport, and tail assembly. PLoS Genet 8: e1002969. doi: 10.1371/journal.pgen.1002969 23055941
30. Lin YH, Lin YM, Teng YN, Hsieh TY, Lin YS, et al. (2006) Identification of ten novel genes involved in human spermatogenesis by microarray analysis of testicular tissue. Fertil Steril 86: 1650–1658. doi: 10.1016/j.fertnstert.2006.04.039 17074343
31. Lin YH, Lin YM, Kuo YC, Wang YY, Kuo PL (2011) Identification and characterization of a novel Rab GTPase-activating protein in spermatids. Int J Androl 34: e358–367. doi: 10.1111/j.1365-2605.2010.01126.x 21128978
32. Lin YH, Ke CC, Wang YY, Chen MF, Chen TM, et al. (2017) RAB10 Interacts with the Male Germ Cell-Specific GTPase-Activating Protein during Mammalian Spermiogenesis. Int J Mol Sci 18.
33. Organization WH (2010) WHO laboratory manual for the Examination and processing of human semen.
34. Wang YY, Chiang HS, Cheng CY, Wu YN, Lin YC, et al. (2017) SLC9A3 Protein Is Critical for Acrosomal Formation in Postmeiotic Male Germ Cells. Int J Mol Sci 19.
35. Kuo PL, Chiang HS, Wang YY, Kuo YC, Chen MF, et al. (2013) SEPT12-microtubule complexes are required for sperm head and tail formation. Int J Mol Sci 14: 22102–22116. doi: 10.3390/ijms141122102 24213608
36. Yeh CH, Kuo PL, Wang YY, Wu YY, Chen MF, et al. (2015) SEPT12/SPAG4/LAMINB1 complexes are required for maintaining the integrity of the nuclear envelope in postmeiotic male germ cells. PLoS One 10: e0120722. doi: 10.1371/journal.pone.0120722 25775403
37. Dunleavy JEM, Okuda H, O'Connor AE, Merriner DJ, O'Donnell L, et al. (2017) Katanin-like 2 (KATNAL2) functions in multiple aspects of haploid male germ cell development in the mouse. PLoS Genet 13: e1007078. doi: 10.1371/journal.pgen.1007078 29136647
38. Platts AE, Dix DJ, Chemes HE, Thompson KE, Goodrich R, et al. (2007) Success and failure in human spermatogenesis as revealed by teratozoospermic RNAs. Hum Mol Genet 16: 763–773. doi: 10.1093/hmg/ddm012 17327269
39. Bos JL (2005) Linking Rap to cell adhesion. Curr Opin Cell Biol 17: 123–128. doi: 10.1016/j.ceb.2005.02.009 15780587
40. Terada K, Kanazawa M, Yano M, Hanson B, Hoogenraad N, et al. (1997) Participation of the import receptor Tom20 in protein import into mammalian mitochondria: analyses in vitro and in cultured cells. FEBS Lett 403: 309–312. doi: 10.1016/s0014-5793(97)00070-7 9091323
41. Goping IS, Millar DG, Shore GC (1995) Identification of the human mitochondrial protein import receptor, huMas20p. Complementation of delta mas20 in yeast. FEBS Lett 373: 45–50. doi: 10.1016/0014-5793(95)01010-c 7589431
42. Seki N, Moczko M, Nagase T, Zufall N, Ehmann B, et al. (1995) A human homolog of the mitochondrial protein import receptor Mom19 can assemble with the yeast mitochondrial receptor complex. FEBS Lett 375: 307–310. doi: 10.1016/0014-5793(95)01229-8 7498524
43. Zhang YJ, O'Neal WK, Randell SH, Blackburn K, Moyer MB, et al. (2002) Identification of dynein heavy chain 7 as an inner arm component of human cilia that is synthesized but not assembled in a case of primary ciliary dyskinesia. J Biol Chem 277: 17906–17915. doi: 10.1074/jbc.M200348200 11877439
44. Neesen J, Koehler MR, Kirschner R, Steinlein C, Kreutzberger J, et al. (1997) Identification of dynein heavy chain genes expressed in human and mouse testis: chromosomal localization of an axonemal dynein gene. Gene 200: 193–202. doi: 10.1016/s0378-1119(97)00417-4 9373155
45. Sullivan R, Mieusset R (2016) The human epididymis: its function in sperm maturation. Hum Reprod Update 22: 574–587. doi: 10.1093/humupd/dmw015 27307387
46. Thimon V, Frenette G, Saez F, Thabet M, Sullivan R (2008) Protein composition of human epididymosomes collected during surgical vasectomy reversal: a proteomic and genomic approach. Hum Reprod 23: 1698–1707. doi: 10.1093/humrep/den181 18482993
47. Ke CC, Lin YH, Wang YY, Wu YY, Chen MF, et al. (2018) TBC1D21 Potentially Interacts with and Regulates Rap1 during Murine Spermatogenesis. Int J Mol Sci 19.
48. Cole A, Meistrich ML, Cherry LM, Trostle-Weige PK (1988) Nuclear and manchette development in spermatids of normal and azh/azh mutant mice. Biol Reprod 38: 385–401. doi: 10.1095/biolreprod38.2.385 3282554
49. Kierszenbaum AL (2001) Spermatid manchette: plugging proteins to zero into the sperm tail. Mol Reprod Dev 59: 347–349. doi: 10.1002/mrd.1040 11468770
50. Kierszenbaum AL (2002) Intramanchette transport (IMT): managing the making of the spermatid head, centrosome, and tail. Mol Reprod Dev 63: 1–4. doi: 10.1002/mrd.10179 12211054
51. Pleuger C, Lehti MS, Dunleavy JE, Fietz D, O'Bryan MK (2020) Haploid male germ cells-the Grand Central Station of protein transport. Hum Reprod Update.
52. Dorval G, Kuzmuk V, Gribouval O, Welsh GI, Bierzynska A, et al. (2019) TBC1D8B Loss-of-Function Mutations Lead to X-Linked Nephrotic Syndrome via Defective Trafficking Pathways. Am J Hum Genet 104: 348–355. doi: 10.1016/j.ajhg.2018.12.016 30661770
53. Falace A, Buhler E, Fadda M, Watrin F, Lippiello P, et al. (2014) TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway. Proc Natl Acad Sci U S A 111: 2337–2342. doi: 10.1073/pnas.1316294111 24469796
54. Mucha BE, Hennekam RCM, Sisodiya S, Campeau PM (2015) TBC1D24-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJHet al., editors. GeneReviews((R)). Seattle (WA).
55. Ivanova EL, Mau-Them FT, Riazuddin S, Kahrizi K, Laugel V, et al. (2017) Homozygous Truncating Variants in TBC1D23 Cause Pontocerebellar Hypoplasia and Alter Cortical Development. Am J Hum Genet 101: 428–440. doi: 10.1016/j.ajhg.2017.07.010 28823707
56. Liegel RP, Handley MT, Ronchetti A, Brown S, Langemeyer L, et al. (2013) Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet 93: 1001–1014. doi: 10.1016/j.ajhg.2013.10.011 24239381
57. Varnum DS (1983) Blind-sterile: a new mutation on chromosome 2 of the house mouse. J Hered 74: 206–207. doi: 10.1093/oxfordjournals.jhered.a109768 6863898
58. Park AK, Liegel RP, Ronchetti A, Ebert AD, Geurts A, et al. (2014) Targeted disruption of Tbc1d20 with zinc-finger nucleases causes cataracts and testicular abnormalities in mice. BMC Genet 15: 135. doi: 10.1186/s12863-014-0135-2 25476608
59. Chang WL, Cui L, Gu Y, Li M, Ma Q, et al. (2019) TBC1D20 deficiency induces Sertoli cell apoptosis by triggering irreversible endoplasmic reticulum stress in mice. Mol Hum Reprod 25: 773–786. doi: 10.1093/molehr/gaz057 31633178
Článek vyšel v časopise
PLOS Genetics
2020 Číslo 9
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Proč při poslechu některé muziky prostě musíme tančit?
- Chůze do schodů pomáhá prodloužit život a vyhnout se srdečním chorobám
- Metamizol jako analgetikum první volby: kdy, pro koho, jak a proč?
- „Jednohubky“ z klinického výzkumu – 2024/44
Nejčtenější v tomto čísle
- Alleviating chronic ER stress by p38-Ire1-Xbp1 pathway and insulin-associated autophagy in C. elegans neurons
- Cocoonase is indispensable for Lepidoptera insects breaking the sealed cocoon
- A mega-analysis of expression quantitative trait loci in retinal tissue
- Adiponectin GWAS loci harboring extensive allelic heterogeneity exhibit distinct molecular consequences