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. The cognate hormones, lutropin/choriogonadotropin (LH/CG) and follitropin are widely used in the treatment of infertility.

Research in my laboratory is driven by the hypothesis that the binding of agonist to the LHR and the FSHR result in the activation of multiple signaling pathways, and that these pathways, either alone or in combination, stimulate the proliferation and differentiated functions of their respective target cells (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 and FSHR-induced activation of mitogenic signaling cascades. (2) Determine how the activation of two homologous receptors (LHR and FSHR) results in the expression of different phenotypes in granulosa cells. (3) Characterize the involvement of the inositol phosphate and the MEK/ERK signaling cascades on the proliferation and differentiation of Leydig and granulosa cells.

Experimental systems used in my laboratory include a Leydig tumor cell that can be readily manipulated using standard transfection protocols, primary cultures of granulosa or Leydig cells that can be readily manipulated using adenoviral vectors and genetically-modified mouse models.

Representative Publications:

Tai P, Shiraishi K, Ascoli M 2009 Activation of the lutropin/choriogonadotropin receptor (LHR) inhibits apoptosis of immature leydig cells in primary culture. Endocrinology doi:10.1210/en.2009-0207

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 149:5549-5556, 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 314:25-37, 2008.

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