Catenins: A role in spertmatogenesis and sperm maturation

Summary

Principal Investigator: MANJEET KUMAR RAO
Abstract: Ectoplasmic specializations are specialized actin-based adherens junctional complexes formed between Sertoli cells (basal ES) and between Sertoli and germ cells (apical ES) in the testis. The importance of this junctional complex is evidenced by the fact that the abnormal or disrupted ES contributes to spermatid sloughing and oligospermia in pathological conditions associated with reduced fertility potential, including varicocele, hyperprolactinemia, diabetes and idiopathic oligospermia. The greater vulnerability of ES to alterations in testis microenvironment compared to other junctional complexes, may explain why ES is frequently disrupted in cases of impaired fertility. Therefore, identification of the regulatory molecules and signaling pathways that regulate ES dynamics is vital to understand the mechanism of ES susceptibility and its role in male fertility. Recently, we have obtained interesting results that show signaling protein "-catenin, which is highly expressed in the germ cells and Sertoli cells, to play an important role in regulating germ cell- Sertoli cell adhesion at the apical ES. We show that spermatid-specific deletion of -catenin not only results in spermatid sloughing (indicating an impaired apical ES), but also causes significantly reduced sperm count and increased germ cell apoptosis. These results led us to hypothesize that -catenin is the molecular link that integrates Sertoli cells-germ cells adhesion with the signaling events essential for germ cell development and maturation. We propose that binding of germ cell -catenin-complex to -catenin-complex on Sertoli cell at the apical ES surface triggers a signaling cascade that regulates post-meiotic germ cell differentiation. Two specific aims are proposed to test these hypotheses: (1) To elucidate the function of -catenin in germ cell development and maturation by targeting events at the apical ectoplasmic specialization. In this aim, we are targeting events only at the apical ES by generating protamine 1 (Prm1) promoter driven conditional knockout mice that specifically silences -catenin in elongating spermatids, thereby distinguishing the events occurring at the cell lumen from those at the base of the cell. (2) To identify and characterize signaling pathways regulated by -catenin at the apical ES. In this aim, by performing microarray analysis, we will identify and characterize -catenin regulated genes to determine specific roles they might play in regulating apical ES functions. The results of this basic research will provide insights into the role of ES in male fertility and a better understanding of the mechanisms by which defects in these critical pathways lead to infertility. In addition, these studies could lead to new insights for therapeutically compromising germ cell movement in the seminiferous epithelium, thereby disrupting spermatogenesis, as a novel approach to reversible male contraception.
Funding Period: ----------------2009 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc The transcription factor Wilms tumor 1 confers resistance in myeloid leukemia cells against the proapoptotic therapeutic agent TRAIL (tumor necrosis factor α-related apoptosis-inducing ligand) by regulating the antiapoptotic protein Bcl-xL
    Hima Bansal
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229, USA
    J Biol Chem 287:32875-80. 2012
  2. pmc Androgen-responsive microRNAs in mouse Sertoli cells
    Subbarayalu Panneerdoss
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
    PLoS ONE 7:e41146. 2012
  3. pmc Isolation of Sertoli, Leydig, and spermatogenic cells from the mouse testis
    Yao Fu Chang
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
    Biotechniques 51:341-2, 344. 2011
  4. pmc Role of β-catenin in post-meiotic male germ cell differentiation
    Yao Fu Chang
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
    PLoS ONE 6:e28039. 2011
  5. pmc Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation
    Yao Fu Chang
    Greehey Children s Cancer Research Institute and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
    Proc Natl Acad Sci U S A 109:5750-5. 2012

Scientific Experts

  • MANJEET KUMAR RAO
  • Yao Fu Chang
  • Subbarayalu Panneerdoss
  • Jennifer S Lee-Chang
  • Hima Bansal
  • Amiya P Sinha-Hikim
  • Sarah S Subaran
  • Carlos Bachier
  • Gail Tomlinson
  • Huizhen Wang
  • Sanjay Bansal
  • Myriam Gorospe
  • Yidong Chen
  • Kalyan C Buddavarapu
  • Hung I Harry Chen
  • Gunapala Shetty
  • Kalyan Chakravarthy Buddavarapu
  • J Saadi Imam
  • Theresea Seifert
  • T Rajendra Kumar
  • Swaminathan Padmanabhan Iyer
  • Krystle Y Harris
  • James A Maclean

Detail Information

Publications6

  1. pmc The transcription factor Wilms tumor 1 confers resistance in myeloid leukemia cells against the proapoptotic therapeutic agent TRAIL (tumor necrosis factor α-related apoptosis-inducing ligand) by regulating the antiapoptotic protein Bcl-xL
    Hima Bansal
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas 78229, USA
    J Biol Chem 287:32875-80. 2012
    ..Collectively, our results suggest that WT1-dependent Bcl-xL overexpression contributes to TRAIL resistance in myeloid leukemias...
  2. pmc Androgen-responsive microRNAs in mouse Sertoli cells
    Subbarayalu Panneerdoss
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
    PLoS ONE 7:e41146. 2012
    ....
  3. pmc Isolation of Sertoli, Leydig, and spermatogenic cells from the mouse testis
    Yao Fu Chang
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
    Biotechniques 51:341-2, 344. 2011
    ..Our protocol combines rigorous enzymatic digestion of seminiferous tubules with counter-current centrifugal elutriation, yielding specific testicular cell populations with >80%-95% purity...
  4. pmc Role of β-catenin in post-meiotic male germ cell differentiation
    Yao Fu Chang
    Greehey Children s Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America
    PLoS ONE 6:e28039. 2011
    ....
  5. pmc Interaction between microRNAs and actin-associated protein Arpc5 regulates translational suppression during male germ cell differentiation
    Yao Fu Chang
    Greehey Children s Cancer Research Institute and Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
    Proc Natl Acad Sci U S A 109:5750-5. 2012
    ....