title: Human X-linked Intellectual Disability Factor CUL4B Is Required for Post-meiotic Sperm Development and Male Fertility.
abstract: In this study, we demonstrate that an E3-ubiquitin ligase associated with human X-linked intellectual disability, CUL4B, plays a crucial role in post-meiotic sperm development. Initially, Cul4b(Δ)/Y male mice were found to be sterile and exhibited a progressive loss in germ cells, thereby leading to oligoasthenospermia. Adult Cul4b mutant epididymides also contained very low numbers of mature spermatozoa, and these spermatazoa exhibited pronounced morphological abnormalities. In post-meiotic spermatids, CUL4B was dynamically expressed and mitosis of spermatogonia and meiosis of spermatocytes both appeared unaffected. However, the spermatids exhibited significantly higher levels of apoptosis during spermiogenesis, particularly during the acrosome phase through the cap phase. Comparative proteomic analyses identified a large-scale shift between wild-type and Cul4b mutant testes during early post-meiotic sperm development. Ultrastructural pathology studies further detected aberrant acrosomes in spermatids and nuclear morphology. The protein levels of both canonical and non-canonical histones were also affected in an early spermatid stage in the absence of Cul4b. Thus, X-linked CUL4B appears to play a critical role in acrosomal formation, nuclear condensation, and in regulating histone dynamics during haploid male germ cell differentiation in relation to male fertility in mice. Thus, it is possible that CUL4B-selective substrates are required for post-meiotic sperm morphogenesis.
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Chih-Hsiang
authors.initials: CH
authors.lastname: Yu
authors.affiliation: Laboratory Animal Center, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: I-Shing
authors.initials: IS
authors.lastname: Yu
authors.affiliation: Department of Bioscience Technology, College of Science, Chung-Yuan Christian University, Taoyuan, Taiwan.
authors.forename: Shu-Rung
authors.initials: SR
authors.lastname: Lin
authors.affiliation: Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: June-Tai
authors.initials: JT
authors.lastname: Wu
authors.affiliation: Graduate Institute of Basic Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Ying-Hung
authors.initials: YH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Obstetrics and Gynecology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Pao-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Jui-Ching
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan.|Department of Laboratory Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.|Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Shu-Wha
authors.initials: SW
authors.lastname: Lin
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D044842:Cullin Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D050172:Genes, X-Linked; D006238:Haploidy; D006657:Histones / Q000378:metabolism; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D021381:Protein Transport; D013087:Spermatids / Q000166:cytology / Q000378:metabolism; D013091:Spermatogenesis / Q000235:genetics*; D013094:Spermatozoa / Q000166:cytology / Q000378:metabolism / Q000473:pathology
chemical_list: C524851:Cul4B protein, mouse; D044842:Cullin Proteins; D006657:Histones
references.citation: Endocr Rev. 2002 Dec;23(6):735-62
references.pmid: 12466187
references.citation: Nat Rev Genet. 2002 Oct;3(10):790-801
references.pmid: 12360237
references.citation: Biol Reprod. 2003 Mar;68(3):837-45
references.pmid: 12604633
references.citation: Microsc Res Tech. 2003 May 1;61(1):88-102
references.pmid: 12672125
references.citation: J Steroid Biochem Mol Biol. 2003 Jun;85(2-5):175-82
references.pmid: 12943702
references.citation: Mech Dev. 2002 Dec;119 Suppl 1:S97-S101
references.pmid: 14516668
references.citation: Int Rev Cytol. 2004;237:1-56
references.pmid: 15380665
references.citation: Endocr Rev. 2004 Oct;25(5):747-806
references.pmid: 15466940
references.citation: Mol Cell Biol. 1985 Jun;5(6):1307-17
references.pmid: 2863747
references.citation: Genes Dev. 1989 Jun;3(6):793-802
references.pmid: 2744463
references.citation: Reproduction. 2005 Mar;129(3):263-8
references.pmid: 15749953
references.citation: Biol Reprod. 2006 Jan;74(1):102-8
references.pmid: 16162871
references.citation: Cell Cycle. 2006 Jan;5(1):71-7
references.pmid: 16322693
references.citation: Physiol Genomics. 2006 Jan 12;24(2):75-85
references.pmid: 16291737
references.citation: Mol Cell. 2006 May 5;22(3):383-94
references.pmid: 16678110
references.citation: Mol Reprod Dev. 2006 Nov;73(11):1430-4
references.pmid: 16894549
references.citation: Am J Hum Genet. 2007 Feb;80(2):345-52
references.pmid: 17236139
references.citation: Am J Hum Genet. 2007 Mar;80(3):561-6
references.pmid: 17273978
references.citation: Nature. 2007 Mar 29;446(7135):562-6
references.pmid: 17392787
references.citation: Development. 2007 May;134(10):1823-31
references.pmid: 17329371
references.citation: J Biosci. 2007 Sep;32(6):1133-8
references.pmid: 17954973
references.citation: Am J Pathol. 2009 May;174(5):1857-68
references.pmid: 19359518
references.citation: Mol Cell Endocrinol. 2009 Jul 10;306(1-2):24-32
references.pmid: 19481682
references.citation: Trends Biochem Sci. 2009 Nov;34(11):562-70
references.pmid: 19818632
references.citation: J Biol Chem. 2009 Nov 27;284(48):33320-32
references.pmid: 19801544
references.citation: Am J Med Genet A. 2010 Jan;152A(1):175-80
references.pmid: 20014135
references.citation: FEBS J. 2010 Feb;277(3):599-604
references.pmid: 20015078
references.citation: Dev Cell. 2010 Mar 16;18(3):371-84
references.pmid: 20153262
references.citation: Hum Mol Genet. 2010 Apr 1;19(7):1324-34
references.pmid: 20064923
references.citation: Zhonghua Nan Ke Xue. 2010 Oct;16(10):867-71
references.pmid: 21243747
references.citation: Dev Biol. 2011 Apr 15;352(2):278-87
references.pmid: 21291880
references.citation: Acta Biochim Biophys Sin (Shanghai). 2011 May;43(5):339-45
references.pmid: 21444325
references.citation: Dev Biol. 2011 Aug 1;356(1):51-62
references.pmid: 21624359
references.citation: Mech Ageing Dev. 2011 Aug;132(8-9):366-73
references.pmid: 21352845
references.citation: J Mol Biol. 2011 Oct 21;413(2):430-7
references.pmid: 21903097
references.citation: Cell. 2011 Oct 14;147(2):459-74
references.pmid: 21963094
references.citation: Mol Cell Proteomics. 2012 Mar;11(3):M111.014407
references.pmid: 22038470
references.citation: PLoS One. 2012;7(5):e37070
references.pmid: 22606329
references.citation: Cell Res. 2012 Aug;22(8):1258-69
references.pmid: 22453236
references.citation: Cell. 2012 Aug 17;150(4):673-84
references.pmid: 22901802
references.citation: Mol Aspects Med. 2012 Oct-Dec;33(5-6):676-90
references.pmid: 22343019
references.citation: Hum Mol Genet. 2012 Oct 1;21(19):4270-85
references.pmid: 22763239
references.citation: Biochim Biophys Acta. 2012 Dec;1822(12):1838-50
references.pmid: 22366765
references.citation: BMC Neurosci. 2012;13:112
references.pmid: 22992378
references.citation: Mol Cell Proteomics. 2012 Dec;11(12):1541-50
references.pmid: 22962057
references.citation: Cancer Cell. 2012 Dec 11;22(6):781-95
references.pmid: 23238014
references.citation: Contraception. 2013 Mar;87(3):296-9
references.pmid: 22995542
references.citation: J Assist Reprod Genet. 2013 Apr;30(4):487-95
references.pmid: 23359247
references.citation: Cell Rep. 2013 Jun 27;3(6):2179-90
references.pmid: 23791531
references.citation: J Biol Chem. 2013 Oct 11;288(41):29550-61
references.pmid: 23913683
references.citation: Cell. 2013 Nov 7;155(4):817-29
references.pmid: 24209620
references.citation: Science. 2013 Dec 20;342(6165):1518-21
references.pmid: 24357321
references.citation: BMC Genomics. 2014;15:39
references.pmid: 24438502
references.citation: Biochim Biophys Acta. 2014 Mar;1839(3):155-68
references.pmid: 24091090
references.citation: Mol Med Rep. 2014 Oct;10(4):2009-24
references.pmid: 25109358
references.citation: Oncogene. 2015 Jan 2;34(1):104-18
references.pmid: 24292684
references.citation: Mol Hum Reprod. 2015 Feb;21(2):195-205
references.pmid: 25371539
references.citation: PLoS Genet. 2015 Feb;11(2):e1004964
references.pmid: 25675407
references.citation: J Cell Sci. 2015 May 1;128(9):1732-45
references.pmid: 25795299
references.citation: Nat Commun. 2015;6:8017
references.pmid: 26281983
references.citation: Toxicol Pathol. 2002 Jul-Aug;30(4):524-33
references.pmid: 12187944
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99 Suppl 4:16477-84
references.pmid: 12177448