Receptors and Signal Transduction / Cellular and Molecular Endocrinology

The lutropin/choriogonadotropin (LHR) and follitropin (FSHR) receptors are the principal regulators of reproduction in humans. Loss-of-function and gain-of-function mutations of these receptors are known to be associated with a number of disorders of the reproductive system such as ovarian dysgenesis, ovarian hyperstimulation syndrome, Leydig cell hypoplasia, male-limited precocious puberty and Leydig cell tumors. In addition, the cognate hormones, lutropin/choriogonadotropin (LH/CG) and follitropin (FSH) are widely used in the treatment of infertility.

Research in my laboratory is geared towards elucidating the signaling pathways activated by the LHR and FSHR that stimulate the proliferation and differentiated functions of Leydig and granulosa cells. Some of the projects that we are currently working on are as follows. (1) Examine the involvement of G protein-dependent and G protein-independent pathways on the LHR-induced activation of mitogenic signaling cascades in Leydig cells. (2) Examine the involvement of the Src-family of kinases and the epidermal growth factor (EGF) network on the proliferative and differentiating functions of the LHR and FSHR. (3) Determine the reasons why the activation of two homologous receptors (LHR and FSHR) results in the expression of different phenotypes in granulosa cells.

These studies are performed using immortalized cell lines, primary cultures of Leydig or granulosa cells and genetically engineered mouse models with global or tissue specific ablation of selected signaling molecules.

Representative Publications:

C. Galet and M. Ascoli.: Arrestin-3 is essential for the activation of Fyn by the luteinizing hormone receptor (LHR) in MA-10 cells. Cell. Signal. 20(10:1822-1829, 2008.

N. Andric and M. Ascoli.: The lutropin receptor activated ERK1/2 cascade stimulates epiregulin release from granulosa cells. Endocrinology. doi:10.1210/en.2008-0618, 2008.

K. Shiraishi and M. Ascoli: A co-culture system reveals the involvement of intercellular pathways as mediators of the lutropin receptor (LHR)-stimulated ERK1/2 phosphorylation in Leydig cells.  Exp. Cell. Res. doi:10.1016/j.yexcr.2007.06.025, 2007.

K. Shiraishi and M. Ascoli:  Lutropin choriogonadotropin (LH/CG) stimulate the proliferation of primary cultures of rat Leydig cells through a pathway that involves activation of the ERK1/2 cascade.  Endocrinology 148:3214-3225, 2007.

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