The endocrine regulation of sertoli cell function

Abstract

The ‘nurse’ cell of the testis, known as the Sertoli cell, directs testicular differentiation, development and fertility; endocrine signalling upon the Sertoli cell is essential for male fertility. This thesis examines how the Sertoli cell responds to endocrine signalling, particularly the molecular and cellular effects of acute hormone suppression. Using an acute model of FSH and testosterone suppression in rats, this thesis identifies hormonally regulated expression of a class of non-coding RNA, known as micro-RNAs (miRNA) within the Sertoli cell. By analysing the predicted functions of regulated miRNA, a novel role for FSH and testosterone signalling upon the formation of the tubulobulbar complex (TBC) is described. Loss of the TBC function upon hormone suppression likely impedes the removal of adhesive junctions between the Sertoli cell and the spermatid, which may contribute to spermiation failure. To determine the function of systemic activin upon Sertoli cell function, a mouse model with activin A over-expression from a distal site identifies a novel effect of activin signalling upon established adult spermatogenesis. This thesis demonstrates that activin induces a hypospermatogenic phenotype in the mouse testis, with circulating activin concentration found to directly correlate with testis mass. Significantly, activin was shown to regulate BTB function and Sertoli cell maturity in primary cell cultures. As such, activin is the first identified factor capable of re-programming Sertoli cells to an immature, de-differentiated phenotype. These findings transform the traditional view about the nature of ‘terminally’ differentiated Sertoli cells in non-seasonal breeding animals and implicate Sertoli cell ‘de-differentiation’ in some forms of infertility and testicular dysgenesis. The findings of this thesis produce a paradigm shift in understanding Sertoli cell biology. Importantly, the data presented offer significant insights into the endocrine regulation of Sertoli cell maturation and function. This is of particular importance to the aetiology of infertility and the development of novel male contraceptive regimes.