NEUROENDOCRINE PEPTIDES/ RECEPTORS REGULATE GONADOTROPHS

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Activins and inhibins are members of the TGFbeta family of growth and differentiation that were discovered by virtue of their reciprocal effects on the production of FSH. These pleiotropic proteins play a wide variety of endocrine, paracrine and autocrine roles within normal and neoplastic reproductive and other tissues. The binding of activin to its specific type II receptor serine kinase kinase (RSK) leads to the recruitment and trans- phosphorylation of its cognate type I RSK (Activin Like Kinase-4) and the subsequent phosphorylation of downstream mediators, the pathway- specific Smads. Under Aim I, we will examine the nature of the interactions between the components of activin signaling. Based on the elucidation of the structure of the ligand binding domain of the type II activin receptor by Project III, we are expressing a series of mutant receptors in mammalian cells and analyzing their affinities for activin, inhibin and the type I receptor (ALK4). These efforts are highly complementary to Choe (Project III), who is working to solve the structure of the ActRII/activin/ALK4 complex and to Fischer (Project IV) who is mutating activin itself.. The second Aim involves the study of mechanisms that serve to limit the biological effects of activin itself. We have observed cellular desensitization of the transcriptional response to activin and will explore mechanisms, including the possibility that this is mediated by the inhibitory Smad, Smad7. We will continue to explore the mode of action of inhibin; this will include a continued effort to clone an inhibin specific binding component. If we are successful, a series of biochemical and cellular experiments will ensure to determine the importance of this protein. If warranted, we will generate and analyze mice deficient in the inhibin receptor. Under Aim III we will continue to explore paracrine and autocrine mechanisms within the pituitary, examining the interesting possibility that some cytokine effects may be mediated through increased production of follistatin. The roles and regulation of Smad7 in the pituitary and gonadotropes, will be explored by a variety of approaches, including the generation of Smad 7 null mice, in which, Smad7 is conditionally knocked out in gonadotropes. This intra-pituitary modulatory network provides a mechanism for the integration of central and peripheral inputs and may be critical for the differential production of FSH and LH under defined physiological circumstances. Drugs and other approaches targeting components of the extracellular and intracellular activin signaling system may prove to be useful for the management of human fertility and reproductive disorders.