Fertility in the male depends on availability of adequate numbers of viable sperm, cells that ultimately arise from the neonatal germ cells, or gonocytes. These cells are mitotically arrested at birth, and apparently reenter the cell cycle shortly thereafter. Fertility also requires sufficient numbers of differentiated Sertoli cells which support germ cell development in adults and which themselves comprise a non-renewable, terminally differentiated population. However, in spite of the importance of normal maturation of both of these populations, we know little about how onset of germ cell development is regulated, and we have no understanding of how terminal differentiation of Sertoli cells is controlled. The overall goal of the proposed studies is to investigate cellular and molecular events that are important for development of both gonocytes and Sertoli cells. In particular, we will identify the basis for contact-based interactions between these cells during this critical period and study the impact of these interactions on survival of germ cells, on their progress through the cell cycle, and on attainment of maturity by Sertoli cells.
Three specific aims are proposed: 1) To define cadherin- and/or integrin-based gonocyte-Sertoli cell interactions in vivo and in vitro, to identify functions in gonocytes regulated by these interactions, and to determine directly if appropriate expression of cadherins/integrins is critical for gonocyte survival. 2) To identify and characterize gonocytes that re-enter the cell cycle and to determine how contact-mediated interaction with differentiating Sertoli cells regulates this entry. 3) To explore onset and regulation of differentiation in Sertoli cells by 1] identifying Sertoli cells that exit the cell cycle during neonatal development and 2] exploring mechanisms that regulate this likely first step in Sertoli cell differentiation. Throughout these studies, we will rely heavily on a well- characterized, defined co-culture system in which onset of germ cell development occurs much as it does in vivo. However, we will also explore interaction between these cells in vivo, in normal animals as well as in animal models where Sertoli cell development is accelerated or delayed. Moreover, since both cell populations are doubtless heterogenous and contain cells in various stages of development, we will rely heavily on visual approaches to analyze individual cells and to identify the basis for and impact of signalling between Sertoli cells and gonocytes.
Showing the most recent 10 out of 18 publications
