Department of Physiology and Cell Biiology

 

 

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Wei Yan, M.D., Ph. D.

Professor

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Scanning electron microscopic images of sperm from wild-type (left) and Spem1-null (right) mice. Scale bar = 10µm (Photo by Wei Yan).

Regulation of Mammalian Gametogenesis

We are interested in how gametes, sperm and oocytes, are produced in mammals. In particular, we investigate which of the germ cell-specific genes are essential for successful production of gametes and which particular molecular pathways they are involved in. We utilize gene knockout technologies and molecular biology approaches to define physiological roles of these genes and the molecular mechanisms by which they regulate germ cell development. Currently, our efforts are focused on the following three topics: (1) the regulation of protein turnover by ubiquitination during spermiogenesis; (2) the control of cytoplasm removal during sperm individualization and spermiation (sperm release); (3) physiological roles of germ cell-specific small non-coding RNAs. Our study is important not only for the identification of causative genes of human infertility, but also for the development of non-hormonal contraceptives.

Search For Dr Yan's Publications In PubMed


Selected Publications

  1. Jiang XH, Yan W (1993) Parentage determination of placental tissues through DNA fingerprints. Annals of Academy of Medicine 22:8-10
  2. Sun YX, Zhao GC, Yan W (1995) Age estimation on the female sternum by quantification theory and stepwise regression analysis. Forensic Science International 74:57-62
  3. He P, Nata M, Kanetake J, Ji G, Yan W, Li X, Sagisaka K (1997) Polymorphism of short tandem repeat (STR) loci PLA2, D3S2459, D8S315 (kw38), CYP19, D3S1359, FGA, and D8S1132 in the Japanese and Chinese populations. Tohoku Journal of Experimental Medicine 183:251-262
  4. Yan W, West A, Toppari J, Lähdetie J (1997) Stage-specific expression and phosphorylation of retinoblastoma protein (pRb) in the rat seminiferous epithelium. Molecular and Cellular Endocrinology 132:137-148
  5. Nata M, Kimura T, Hashiyada M, He P, Yan W, Li X, Funayama M, Sagisaka K (1999) Allele frequencies of eight STRs in Japanese and Chinese. International Journal of Legal Medicine 112:396-399
  6. Hakovirta H*, Yan W*, Kaleva M, Zhang F, Vänttinen K, Morris PL, Söder O, Parvinen M, Toppari J (1999) Function of stem cell factor as a survival factor of spermatogonia and localization of messenger ribonucleic acid in the rat seminiferous epithelium. Endocrinology 140:1492-1498 (*co-first authors)
  7. Yan W, Linderborg J, Suominen J, Toppari J (1999) Stage-specific regulation of stem cell factor (SCF) gene expression in the rat seminiferous epithelium. Endocrinology 140:1499-1504
  8. Moilanen AM, Karvonen U, Poukka H, Yan W, Toppari J, Jänne OA, Palvimo J (1999) A testis-specific androgen receptor coregulator that belongs to a novel family of nuclear proteins. Journal of Biological Chemistry 274:3700-3704
  9. Schultz R, Yan W, Toppari J, Völkl A, Gustafsson J, Huikko MP (1999) Expression of peroxisome proliferator-activated receptor ? mRNA and protein in human and rat testis. Endocrinology 140:2968-2975)
  10. Tena-Sempere M, Kero J, Rannikko A, Yan W, Huhtaniemi I (1999) The pattern of inhibin/activin ? and ?B subunit mRNA expression in rat testis after selective Leydig cell destruction by ethylene dimethane sulfonate. Endocrinology 140: 5761-5770)
  11. Yan W, Suominen J, Toppari J (2000) Stem cell factor protects germ cells from apoptosis in vitro. Journal of Cell Science 113:161-168
  12. Yan W, Samson M, Jégou B, Toppari J (2000) Bcl-w forms complexes with Bax and Bak and elevated ratios of Bax/Bcl-w and Bak/Bcl-w correspond to spermatogonial and spermatocyte apoptosis in the testis. Molecular Endocrinology 14:682-699
  13. Zheng H, Yan W, Toppari J, Härkönen P (2000) Improved non-radioactive RT-PCR method for relative quantification of mRNA. BioTechniques 28:832-834
  14. Yan W, Kero J, Huhtaniemi I, Toppari J (2000) Stem cell factor functions as a survival factor for mature Leydig cells and a growth factor for precursor Leydig cells after ethylene dimethane sulfonate treatment: implication of the role of stem cell factor/c-kit interaction in Leydig cell development. Developmental Biology 227:169-182
  15. Yan W, Kero J, Suominen J, Toppari J (2001) Differential expression and regulation of retinoblastoma protein (pRb) family members during testicular development and spermatogenesis: a model for the control of germ cell proliferation, differentiation and apoptosis in vivo. Oncogene  20: 1343–1356
  16. Li X, Nokkala E, Yan W, Streng T, Saarinen N, Wärri A, Huhtaniemi I, Santti R, Mäkelä S, Poutanen M (2001) Altered structure and function of reproductive organs in transgenic male mice overexpressing human aromatase and maintaining elevated serum estradiol and low testosterone concentrations. Endocrinology 142:2435–2442
  17. Suominen J, Yan W, Toppari J, Kaipia A (2001) Expression and regulation of Bcl-2-related ovarian killer (Bok) mRNA in the developing and adult rat testis. European Journal of Endocrinology 145:771-778
  18. Blaeser F, Toppari J, Heikinheimo M, Yan W, Wallace M, Ho N, Chatila T (2001) Normal Spermatogenesis in CaMKIV/Gr-Deficient Mice. American Journal of Physiology, Endocrinology, and Metabolism 281: E931-E937
  19. Yan W, Rajkovic A, Viveiros MM, Burns KH, Eppig JJ, Matzuk MM (2002) Identification of Gasz, an evolutionarily conserved gene expressed exclusively in germ cells and encoding a protein with four ankyrin repeats, a sterile-alpha motif, and a basic leucine zipper. Molecular Endocrinology 16: 1168-1184
  20. Rajkovic A, Yan C, Yan W, Klysik M, Matzuk M (2002) Obox, a family of homeobox genes preferentially expressed in germ cells. Genomics 79: 711-717
  21. Yan W, Hirvonen SJ, Palvimo J, Toppari J, Janne OA (2002) Expression of the Nuclear RING Finger Protein SNURF/RNF4 during Rat Testis Development Suggests a Role in Spermatid Maturation. Mechanisms of Development 118: 247-253
  22. Yan W, Burns KH, Ma L, Matzuk MM (2002) Identification of Zfp393, a germ cell-specific gene encoding a novel zinc finger protein. Mechanisms of Development 118: 233-239
  23. Yan W, Burns KH, Matzuk MM (2003) Genetic engineering to study testicular tumorigenesis (Review). APMIS 111: 174-183
  24. Toppari J, Suominen JS, Yan W (2003) The role of retinoblastoma protein family in the control of germ cell proliferation, differentiation, and survival (Review). APMIS 111:245-251
  25. Suzumori N, Burns KH, Yan W, Matzuk MM (2003) RFLP-4 interacts with proteins of the ubiquitin-proteosome degradation pathway in oocytes. Proceedings of the National Academy of Sciences USA 100:550-555
  26. Yan W, Assadi AH, Wynshaw-Boris A, Eichele G, Matzuk MM, Clark GD (2003) A novel role for platelet-activating factor acetylhydrolase 1b in mouse spermatogenesis. Proceedings of the National Academy of Sciences USA 100:7189-7194.
  27. Wu MH, Rajkovic A, Burns KH, Yan W, Lin YN, Matzuk MM (2003) Sequence and expression of testis-expressed gene 14 (Tex 14): a gene encoding a protein kinase expressed exclusively during spermatogenesis. Gene Expression Patterns 3:231-236.
  28. Yan W, Huang JX, Lax AS, Pelliniemi L, Salminen E, Poutanen M, Toppari J (2003) Overexpression of Bcl-w in the testis disrupts spermatogenesis: revelation of a role of BCL-W in male germ cell cycle control. Molecular Endocrinology 17:1868-1879.
  29. Yan W, Ma L, Burns KH, Matzuk MM (2003) Identification of a novel spermatid-specific linker histone H1 involved in chromatin remodeling during mammalian spermiogenesis. Proceedings of the National Academy of Sciences USA 100:10546-10551.
  30. Yan W, Ma L, Burns, KH, Matzuk MM (2004) Haploinsufficiency of KLHL10 causes male infertility. Proceedings of the National Academy of Sciences USA 101:7793-7798.
  31. Yan W, Ma L, Stein P, Pangas SA, Burns KH, Bai, YC, Schultz, RM,, Matzuk, MM (2005) Mice deficient in oocyte-specific oligoadenylate synthetase-like protein OAS1D display reduced fertility. Molecular and Cellular Biology 25:4615-4624.
  32. Jin JL, O’Doherty AM, Wang SH, Zheng HL, Sanders KM, Yan W (2005) Catsper3 and Catsper4 encode two cation channel-like proteins exclusively expressed in the testis. Biology of Reproduction 73:1235-1242
  33. Greenbaum MP, Yan W*, Wu MH, Lin YN, Agno JE, Sharma M, Braun RE, Rajkovic A, Matzuk MM. (2006) TEX14 is essential for intercellular bridges and fertility in male mice. Proceedings of the National Academy of Sciences USA 103(13):4982-7. (*co-first authors)
  34. Yatsenko AN, Roy A, Chen R, Ma L, Murthy LJ, Yan W, Lamb DJ, Matzuk MM (2006) Non-invasive genetic diagnosis of male infertility using spermatozoal RNA: KLHL10 mutations in oligozoospermic patients impair homodimerization. Human Molecular Genetics 15:3411-3419.
  35. Wang SH, Zheng HL, Esaki Y, Kelly F, Yan W (2006) Cullin3 is a KLHL10-interacting protein preferentially expressed during late spermiogenesis. Biology of Reproduction 74:102-108
  36. Ro S, Park C, Song R, Nguyen D, Jin J, Sanders KM, McCarrey JR, Yan W (2007) Cloning and expression profiling of testis-expressed piRNA-like RNAs. RNA   Published August 13, 2007, 10.1261/rna.640307 Download Supplementary Tables Here
  37. Zheng Z, Zheng H, Yan W (2007) Fank1 is a testis-specific gene encoding a nuclear protein exclusively expressed during the transition from the meiotic to the haploid phase of spermatogenesis. Gene expression patterns 7:777-783
  38. Ro S, Park C, Young D, Sanders KM, Yan W (2007) Tissue-dependent paired expression of miRNAs. Nucleic Acids Research  Published online on August 28, 2007, Doi:10.1093/nar/gkm641
  39. Lin YN, Roy A, Yan W, Burns KH, Matzuk MM (2007) Loss of zona pellucida binding proteins in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis. Molecular and Cellular Biology doi:10.1128/MCB.01029-07, published online ahead of print on 30 July 2007
  40. Ro S, Park C, Young D, Sanders KM, McCarrey JR, Yan W (2007) Cloning and expression profiling of testis-expressed microRNAs Developmental Biology311: 604-614
  41. Ro S, Song R, Park C, Zheng H, Sanders KM, Yan W (2007) Cloning and expression profiling of small RNAs expressed in the mouse ovary. RNA   Published online before print October 19, 2007, DOI: 10.1261/rna.754207. Download supplementary data from Here!
  42. Ro S, Park C, Jin J, Sanders KM, Yan W (2006) A PCR-based method for detection and quantification of small RNAs. Biochemical and Biophysical Research Communications 351:756-763.
  43. Zheng H, Stratton CJ, Morozumi K, Jin J, Yanagimachi R, Yan W (2007) Lack of Spem1 causes aberrant cytoplasm removal, sperm deformation and male infertility. Proceedings of the National Academy of Sciences USA  104:6852-6857
  44. Jin J, Jin N, Zheng H, Ro S, Tafolla D, Sanders KM, Yan W (2007) Catsper3 and Catsper4 are essential for sperm hyperactivated motility and male fertility. Biology of Reproduction 77:37-44
  45. Ro S, Park C, Song R, Nguyen D, Jin J, Sanders KM, McCarrey JR, Yan W (2007) Cloning and expression profiling of testis-expressed piRNA-like RNAs. RNA 13:1693-1702
  46. Zheng Z, Zheng H, Yan W (2007) Fank1 is a testis-specific gene encoding a nuclear protein exclusively expressed during the transition from the meiotic to the haploid phase of spermatogenesis. Gene Expression Patterns 7:777-783
  47. Ro S, Park C, Young D, Sanders KM, Yan W (2007) Tissue-dependent paired expression of miRNAs. Nucleic Acids Research 35:5944-5953
  48. Lin YN, Roy A, Yan W, Burns KH, Matzuk MM (2007) Loss of zona pellucida binding proteins in the acrosomal matrix disrupts acrosome biogenesis and sperm morphogenesis. Molecular and Cellular Biology 27:6794-6805
  49. Ro S, Park C, Young D, Sanders KM, McCarrey JR, Yan W (2007) Cloning and expression profiling of testis-expressed microRNAs Developmental Biology 311: 592-602
  50. Ro S, Song R, Park C, Zheng H, Sanders KM, Yan W (2007) Cloning and expression profiling of small RNAs expressed in the mouse ovary. RNA 13:2366-2380
  51. Yan W*, Morozumi K, Zhang J, Ro S, Park C, Yanagimachi R (2008) Birth of mice after intracytoplasmic injection of single purified sperm nuclei and detection of messenger RNAs and microRNAs in the sperm nuclei. Biology of Reproduction 78:896-902 (*corresponding author)
  52. Papaioannou MD, Pitetti JL, Ro S, Park C, Aubry F, Schaad O, Vejnar CE, Descombes P, Zdobnov EM, McManus MT, Guillou F, Harfe BD, Yan W, Jégou B, Nef S (2009) Sertoli cell Dicer is essential for spermatogenesis in mice. Developmental Biology 326:250-259
  53. Song R, Michaels JD, Ro S, McCarrey JR, Yan W (2009) X-linked microRNAs escape meiotic sex chromosome inactivation. Nature Genetics 41:488-493
  54. Yan W (2009) Male Infertility caused by spermiogenic defects: Lessons from gene knockouts. Molecular and Cellular Endocrinology 306:24-32. doi:10.1016/j.mce.2009.03.003.
  55. Ma L, Buchold GM, Greenbaum MP, Roy A, Burns KH, Zhu H, Han DY, Harris RA, Coarfa C, GunaratnePH , Yan W, Matzuk MM (2009) GASZ is Essential for Male Meiosis and Suppression of Retrotransposon Synthesis in the Male Germline. PLoS Genetics 5(9): e1000635. Published online 2009 September 4. doi: 10.1371/journal.pgen.1000635.
  56. Yan W, McCarrey JR (2009) Noise amidst the silence: sex chromosome inactivation in the male. (Review) Epigenetics 4(7):452-456
  57. Zhu MH, Kim TW, Ro S, Yan W, Ward SM, Koh SD, Sanders KM (2009) A Ca(2+)-activated Cl(-) conductance in interstitial cells of Cajal linked to slow wave currents and pacemaker activity. Journal of Physiology 587:4905-4918
  58. Ro S, Park C, Jin J, Zheng H, Blair P, Redelman D, Ward SM, Yan W, Sanders KM (2010) A model to study the phenotypic changes of interstitial cells of Cajal (ICC) in gastrointestinal diseases. Gastroenterology 138(3): 1068-78.e1-2.
  59. Ro S, Yan W (2010) Detection and quantitative analysis of small RNAs by PCR. Methods in Molecular Biology 629:295-305.
  60. Ro S, Yan W (2010) Small RNA cloning. Methods in Molecular Biology 629:273-85.
  61. Song R, Ro S, Yan W (2010) In situ hybridization detection of microRNAs. Methods in Molecular Biology 629:287-94.
  62. Yan W, Slaymaker S, Si Y, Jin J, Zheng H, Aslanian A, Saunders L, Verdin E, Charo IF (2010) Zmynd15 encodes a transcription repressor essential for late spermiogenesis and male fertility. Journal of Biological Chemistry 285:31418-31426.
  63. Bao J, Zhang J, Zheng H, Yan W (2010) Ubiquilin1is localized to the junction of Sertoli cell and developing spermatids. Molecular and Cellular Endocrinology 327:89-97.
  64. Bao J, Zhang J, Song R, Zheng H, Yan W (2011) Ran-binding protein 17 is preferentially expressed in the testis and is associated with the XY body and manchette during spermatogenesis. Molecular and Cellular Endocrinology 333:134-142.
  65. Park C, Yan W, Ward SM, Hwang SJ, Wu Q, Hatton W, Park J, Sanders KM, Ro S (2011) MicroRNAs dynamically remodel gastrointestinal smooth muscle cells. PLoS ONE 6(4): e18628.
  66. Park C, Hennig GW, Sanders KM, Cho JH, Hatton WJ, Redelman D, Park JK, Ward SM, Miano JM, Yan W, Ro S (2011) SRF-dependent microRNAs regulate gastrointestinal smooth muscle cell phenotypes, Gastroenterology 141(1): 164-175.
  67. Song R, Hennig G, Wu Q, Jose C, Zheng H, Yan W (2011) Male germ cells express abundant endogenous siRNAs. Proceedings of the National Academy of Sciences USA. 108:13159-64.
  68. Idler RK, Yan W (2011) Control of messenger RNA fate by RNA binding proteins: an emphasis on mammalian spermatogenesis. (Review) Journal of Andrology 33: 309-337
  69. Bao J, Wang L, Lei J, Hu Y, Liu Y, Shen H, Yan W, Xu C (2011) STK31 (TDRD8) is dynamically regulated throughout mouse spermatogenesis and interacts with MIWI protein. Histochemistry and Cell Biology 137(3): 377-89.
  70. Bao J, Yan W (2012) Male germline control of transposable elements. (Review) Biology of Reproduction 86 (5) 162, 1-14.
  71. Bao J, Li D, Wang L, Wu J, Hu Y, Wang Z, Chen Y, Cao X, Jiang C, Yan W*, Xu C (2012) microRNA-449 and microRNA-34b/c function redundantly in murine testes by targeting the E2F transcription factor-Retinoblastoma protein (E2F-pRb) pathway. Journal of Biological Chemistry 287(26): 21686-21698. (*co-corresponding author)
  72. Wu Q, Song R, Ortogero N, Zheng H, Evanoff R, Small CL, Griswold MD, Namekawa SH, Royo H, Turner JM, Yan W (2012) The RNase III Enzyme DROSHA Is Essential for microRNA Production and Spermatogenesis. Journal of Biological Chemistry 287(30): 25173-25190.
  73. Ortogero N, Hennig GW, Langille C, Ro S, McCarrey JR, Yan W (2012) Computer-Assisted Annotation of the Sertoli Cell Small RNA Transcriptome. Biology of Reproduction 88 (1) 3:1-10. Published ahead of print November 7, 2012, doi:10.1095/biolreprod.112.102269
  74. Idler, KR, Hennig, GW, Yan W (2012) Bioinformatic Identification of Novel Elements Potentially Involved in mRNA Fate Control during Spermatogenesis. Biology of Reproduction 87 (6) 138:1-10. Published ahead of print October 10, 2012, doi: 10.1095/biolreprod.112.102434.
  75. Ro S, Song R, Park C, Hennig GW, Zheng H, Yan W (2012) Mitochondrial genome-encoded small RNAs are essential for normal mitochondrial gene expression. In revision.