Integrating systems biology and transgenic technologies to unlock the secrets of Sertoli cell development and function

Published: 5 September 2014

O'Shaughnessy - Integrating systems biology and transgenic technologies to unlock the secrets of Sertoli cell development and function, BBSRC, 2012 - 2015, £155,700

Adult male fertility and wellbeing are dependent upon appropriate fetal and postnatal testis development. This proposal is designed to develop our fundamental understanding of testis development through a combination of cell ablation studies and generation of a computer modelling system.

Early events in testis development are induced by Sertoli cell (SC) differentiation which leads to formation of the seminiferous tubules and development of the fetal Leydig cells (LC) and peritubular myoid cells (PTMC). We do not know, however, the extent to which the SC remain central to testis biology thereafter, beyond local maintenance of spermatogenesis.

To identify the role of the SC in overall testis biology we have generated a mouse line that expresses the simian diphtheria toxin receptor (DTR) specifically in the Sertoli cells. Mice normally lack a functional DTR so that treatment of these animals with diphtheria toxin (DTX) will lead to specific ablation of the SC. This will allow us to determine what happens to the testis if SC are ablated at different stages of development.

In preliminary experiments with neonatal mice we have shown that a single injection of DTX causes near total SC ablation with no other harmful effects on the mice.

We now propose to use this model system to determine the role of the SC in:

(i) PTMC, LC and gonocyte survival, function and development in the fetus

(ii) adult LC differentiation, development and function and

(iii) PTMC function and differentiated status in the adult animal.

In addition, through partial ablation of the SC, our studies will show how adaptive the remaining SC are during proliferation and following final differentiation. Data from these studies will be integrated into a comprehensive in silico model of testis development and function.

This will enhance our understanding of the ongoing biological processes and will provide the opportunity to test hypotheses related to testis development, function and dysfunction.

First published: 5 September 2014