The major interest in my laboratory is to understand the biochemical basis for the development of sperm function. This knowledge should help in the diagnosis and treatment for male factor infertility. A long-term goal is to develop new approaches to regulate male fertility and understand the causes for infertility, management of fertility in man, domestic animals of economic importance, and endangered animal species.
We showed that a novel signal transduction system is centered around the sperm specific isoform, PP1g2, of the serine/threonine phosphatase. This protein phosphatase isoform, which is highly expressed in testis, is present only in mammalian spermatozoa. Protein regulators of this enzyme include inhibitors I2 (PPP1R2) and I3 (PPP1R11), sds22 (PPP1R7), protein 14-3-3 and a protein kinase, glycogen synthase kinase 3 (GSK-3).
Changes in the activity of PP1g2 and GSK-3 are key events in sperm motility development. Disruption of the gene for PP1g2 results in male infertility. A large part of our work involves understanding how the activity of this enzyme is regulated in testis and during sperm development in the testis and epididymis. Using gene knockout, transgenic and molecular approaches we are investigating the signal mechanisms underlying regulation of protein phosphorylation and sperm function.
Scholarly, Creative & Professional Activities
Freitas MJ, Silva JV, Brothag C, Regadas-Correia B, Fardilha M, Vijayaraghavan S. Isoform-specific GSK3A activity is negatively correlated with human sperm motility. Mol Hum Reprod. 2019 Mar 2. pii: gaz009. doi: 10.1093/molehr/gaz009. [Epub ahead of print] PubMed PMID: 30824926.
Dudiki T, Joudeh N, Sinha N, Goswami S, Eisa A, Kline D, Vijayaraghavan S. The protein phosphatase isoform PP1γ1 substitutes for PP1γ2 to support spermatogenesis but not normal sperm function and fertility. Biol Reprod. 2018 Oct 30. doi: 10.1093/biolre/ioy225. [Epub ahead of print] PubMed PMID: 30379985.
Bhattacharjee R, Goswami S, Dey S, Gangoda M, Brothag C, Eisa A, Woodgett J, Phiel C, Kline D, Vijayaraghavan S. Isoform-specific requirement for GSK3α in sperm for male fertility. Biol Reprod. 2018 Aug 1;99(2):384-394. doi: 10.1093/biolre/ioy020. PubMed PMID: 29385396.
Sinha N, Puri P, Nairn AC, Vijayaraghavan S. Selective ablation of Ppp1cc gene in testicular germ cells causes oligo-teratozoospermia and infertility in mice. Biol Reprod. 2013 Nov 27;89(5):128. doi: 10.1095/biolreprod.113.110239. Print 2013 Nov. PubMed PMID: 24089200; PubMed Central PMCID: PMC4076382.
Soler DC, Kadunganattil S, Ramdas S, Myers K, Roca J, Slaughter T, Pilder SH,Vijayaraghavan S. Expression of Transgenic PPP1CC2 in the Testis of Ppp1cc-Null Mice Rescues Spermatid Viability and Spermiation but Does Not Restore Normal Sperm Tail Ultrastructure, Sperm Motility, or Fertility. Biol Reprod. 81(2):343-52.
Puri P, Myers K, Kline D, Vijayaraghavan S. Proteomic amalysis of bovine sperm YWHA binding partners identify proteins involved in signaling and metabolism. Biol Reprod. 2008Dec;79(6):1183-91. [Pubmed]
Snow AJ, Puri P, Acker-Palmer A, Bouwmeester T, Vijayaraghavan S, Kline D. Phosphorylation-dependent interaction of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein (YWHA) with PADI6 following oocyte maturation in mice.Biol Reprod. 2008 Aug;79(2):337-47.[PubMed]
Chakrabarti R, Cheng L, Puri P, Soler D, Vijayaraghavan S. Protein phosphatase PP1 gamma 2 in sperm morphogenesis and epididymal initiation of sperm motility. Asian J Androl. 2007 Jul;9(4):445-52. [PubMed]
Pilder SH, Lu J, Han Y, Hui L, Samant SA, Olugbemiga OO, Meyers KW, Cheng L, Vijayaraghavan S. The molecular basis of "curlicue": a sperm motility abnormality linked to the sterility of t haplotype homozygous male mice. Soc Reprod Fertil Suppl. 2007;63:123-33. Review. [PubMed]
Vijayaraghavan S, Chakrabarti R, Myers K. Regulation of sperm function by protein phosphatase PP1gamma2. Soc Reprod Fertil Suppl. 2007;63:111-21. Review. [PubMed]
Chakrabarti R, Kline D, Lu J, Orth J, Pilder S, Vijayaraghavan S. Analysis of Ppp1cc-null mice suggests a role for PP1gamma2 in sperm morphogenesis. Biol Reprod. 2007 Jun;76(6):992-1001. Epub 2007 Feb 14. [PubMed]
Bajpai M, Fiedler SE, Huang Z, Vijayaraghavan S, Olson GE, Livera G, Conti M, Carr DW. AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa. Biol Reprod. 2006 Jan;74(1):109-18. Epub 2005 Sep 21. [PubMed]
Huang Z, Somanath PR, Chakrabarti R, Eddy EM, Vijayaraghavan S. Changes in intracellular distribution and activity of protein phosphatase PP1gamma2 and its regulating proteins in spermatozoa lacking AKAP4. Biol Reprod. 2005 Feb;72(2):384-92. [PubMed]
Somanath PR, Jack SL, Vijayaraghavan S. Changes in sperm glycogen synthase kinase-3 serine phosphorylation and activity accompany motility initiation and stimulation. J Androl. 2004 Jul-Aug;25(4):605-17.[PubMed]
Myers K, Somanath PR, Berryman M, Vijayaraghavan S. Identification of chloride intracellular channel proteins in spermatozoa. FEBS Lett. 2004 May 21;566(1-3):136-40. [PubMed]
Huang Z, Myers K, Khatra B, Vijayaraghavan S. Protein 14-3-3zeta binds to protein phosphatase PP1gamma2 in bovine epididymal spermatozoa. Biol Reprod. 2004 Jul;71(1):177-84. [PubMed]
Huang Z, Vijayaraghavan S. Increased phosphorylation of a distinct subcellular pool of protein phosphatase, PP1gamma2, during epididymal sperm maturation. Biol Reprod. 2004 Feb;70(2):439-47. [PubMed]
Mishra S, Somanath PR, Huang Z, Vijayaraghavan S. Binding and inactivation of the germ cell-specific protein phosphatase PP1gamma2 by sds22 during epididymal sperm maturation. Biol Reprod. 2003 Nov;69(5):1572-9. [PubMed]
Huang Z, Khatra B, Bollen M, Carr DW, Vijayaraghavan S. Sperm PP1gamma2 is regulated by a homologue of the yeast protein phosphatase binding protein sds22. Biol Reprod. 2002 Dec;67(6):1936-42.[PubMed]
Vijayaraghavan S, Mohan J, Gray H, Khatra B, Carr DW. A role for phosphorylation of glycogen synthase kinase-3alpha in bovine sperm motility regulation. Biol Reprod. 2000 Jun;62(6):1647-54. [PubMed]
Vijayaraghavan S, Liberty GA, Mohan J, Winfrey VP, Olson GE, Carr DW. Isolation and molecular characterization of AKAP110, a novel, sperm-specific protein kinase A-anchoring protein. Mol Endocrinol. 1999 May;13(5):705-17. [PubMed]
Smith GD, Wolf DP, Trautman KC, Vijayaraghavan S. Motility potential of macaque epididymal sperm: the role of protein phosphatase and glycogen synthase kinase-3 activities. J Androl. 1999 Jan-Feb;20(1):47-53. [PubMed]
Vijayaraghavan S, Olson GE, NagDas S, Winfrey VP, Carr DW. Subcellular localization of the regulatory subunits of cyclic adenosine 3',5'-monophosphate-dependent protein kinase in bovine spermatozoa. Biol Reprod. 1997 Dec;57(6):1517-23. [PubMed]
Vijayaraghavan S, Trautman KD, Goueli SA, Carr DW. A tyrosine-phosphorylated 55-kilodalton motility-associated bovine sperm protein is regulated by cyclic adenosine 3',5'-monophosphates and calcium. Biol Reprod. 1997 Jun;56(6):1450-7.[PubMed]
Vijayaraghavan S, Goueli SA, Davey MP, Carr DW. Protein kinase A-anchoring inhibitor peptides arrest mammalian sperm motility. J Biol Chem. 1997 Feb 21;272(8):4747-52.[PubMed]
Smith GD, Wolf DP, Trautman KC, da Cruz e Silva EF, Greengard P, Vijayaraghavan S. Primate sperm contain protein phosphatase 1, a biochemical mediator of motility. Biol Reprod. 1996 Mar;54(3):719-27. [PubMed]