The Role of TAF4b in Spermatogonial Stem Cell Maintenance and Self-Renewal

Summary

Principal Investigator: Eric Gustafson
Abstract: DESCRIPTION (provided by applicant): Understanding how stem cells balance self-renewal with differentiation is paramount in harnessing their therapeutic potential in medicine. While recent work has identified master transcriptional regulator genes controlling pluripotency in mouse and human embryonic stem (ES) cells, it is still unclear whether similar mechanisms direct cell fate decisions in tissue-specific unipotent stem cells, such as the spermatogonial stem cells (SSCs) found in mammalian testes. In contrast to the master regulator proteins in ES cells, recent works has discovered essential functions for cell type-specific or -enriched forms of the core transcription machinery in regulating gene expression. These are required to drive critical gene expression programs involved in diverse developmental events associated with multicellularity and organogenesis. The diversification of core transcription machinery is most notable in the germline where germ cell-specific or -enriched variants of the general transcription factors TFIIA and TFIID execute highly critical and selective functions in regulating reproduction and fertility. This new paradigm of germ cell-specific gene regulation is conserved between invertebrates and vertebrates, and may reflect an important mechanism for evolving germ cell-specific modes of gene regulation. However, the need to understand the molecular mechanisms underlying such exquisite regulation of fertility persists. The goal of this research proposal is to characterize the role of TAF4b in the establishment and maintenance of the self-renewing lineage of SSCs in the mouse testis. TAF4b is a gonad-enriched general transcription factor varient and both male and female Taf4b-deficient mice exhibit reproductive defects. Several lines of evidence suggest it plays an essential role in spermatogonia stem cell (SSC) self-renewal and longevity. One of the specific aims in this research proposal is to identify and characterize TAF4b-interacting protein cofactors to investigate their function in SSC regulation. One of the ways TAF4b may control SSC-specific gene expression is through direct interaction with other proteins that function to turn appropriate SSC genes on or off. This aim will test this hypothesis by identifying these proteins and analyzing their function in SSC gene expression. The second specific aim is to identify where TAF4b binds in the SSC genome and identify which genes TAF4b is directly targeting for regulation. This will provide mechanistic insight into how TAF4b determines which genes it will regulate, how SSC-specific gene regulatory programs are established and how these programs drive SSC self-renewal. The work proposed here, to uncover the mechanisms of TAF4b in regulating SSC maintenance and self-renewal, will reveal fundamental biological principles underlying both stem cell biology and reproductive functions in men required for fertility. These studies may reveal the etiologies behind unexplained male infertility and lead to advanced diagnostic and therapeutic tools to better address and manage male infertility.
Funding Period: 2013-04-01 - 2016-03-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Evolutionary and Functional Genetics of Male Reproduction using Wild Mice as a Mo
    Matthew D Dean; Fiscal Year: 2013
    ..These four specific aims synergize multiple levels of biological information to gain fundamental insights into the genetic basis of male reproduction. ..
  2. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  3. Transcriptional regulatory networks in spermatogonial stem cells
    BRIAN PETER HERMANN; Fiscal Year: 2013
    ..Moreover, additional nurturing of the candidate's career development will promote a competitive, independent research career to contribute substantively to the biomedical sciences. ..
  4. UC Berkeley/Stanford Children's Enviromental Health Center
    Gary M Shaw; Fiscal Year: 2013
    ..7) To support the data management and QA/QC operations of CHAPS-SJV. 8) To support and implement the data sharing plan. 9) To support the annual CEHC meetings and the travel of CHAPS-SJV investigators to these meetings. ..
  5. B-cell Biology of Mucosal Immune Protection from SIV Challenge
    Eric Hunter; Fiscal Year: 2013
    ....
  6. Molecular and Architectural Mechanisms of Reprogramming to Pluripotency
    Kathrin Plath; Fiscal Year: 2013
    ..The plan provides unique experimental synergies that address the objectives of the funding announcement. ..
  7. Dmrt1 in gonadal sex maintenance
    Robin E Lindeman; Fiscal Year: 2013
    ..The findings from this work should have direct relevance to other examples of cell fate reprogramming and to the diagnosis and treatment of human DSD, infertility, and gonadal cancers. ..
  8. TOXIC SUBSTANCES IN THE ENVIRONMENT
    Martyn T Smith; Fiscal Year: 2013
    ..The program will be overseen and coordinated by an Administration core (A). ..
  9. Genomic Studies Mammalian Y Chromosomes
    David C Page; Fiscal Year: 2013
    ..We anticipate that the sequence of the W chromosome will inform our understanding of human biology by offering insights into female fertility, oogenesis, and sex determination. ..
  10. Neural basis of leptin action on reproduction
    Carol Fuzeti Elias; Fiscal Year: 2013
    ..In addition, we will also assess the requirement of leptin signaling in both (PMV and Kiss1) neuronal population (Aim3) for the full rescue of the infertility phenotype of LepR null mice. ..
  11. Regulation of Rhox5 Transcriptional Elongation
    Marcy E Richardson; Fiscal Year: 2013
    ..The control of these two phenomena will be analyzed in the developmental and tissue-specific program that allows the expression of Rhox5 Pp in the mouse testis. ..
  12. MRNA PROCESSING IN REPRODUCTION AND FERTILIZATION
    Clinton C MacDonald; Fiscal Year: 2013
    ..Using a variety of techniques, we want to learn the molecular causes of why sperm production fails in males missing the CSTF2T gene, to better understand how to assist these infertile couples. ..
  13. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  14. Expanding Excellence in Developmental Biology in Oklahoma
    Linda F Thompson; Fiscal Year: 2013
    ..abstract_text> ..
  15. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  16. Stanford University Center for Reproductive and Stem Cell biology
    Margaret T Fuller; Fiscal Year: 2013
    ..abstract_text> ..
  17. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  18. Clinical and Basic Studies in Polycystic Ovarian Syndrome
    John C Marshall; Fiscal Year: 2013
    ..s. ..
  19. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  20. DMRT1 IN MAMMALIAN SEXUAL DEVELOPMENT
    David A Zarkower; Fiscal Year: 2013
    ..The results of this study should aid in treatment of gonadal cancer and infertility, and will inform studies of cell fate reprogramming and design of novel male contraceptives. ..