TGF-beta superfamily

TGF-beta superfamily

1. BMPs

   • Bmp-15
     • Female subfertility (homozygote), interacts with Gdf-9, required to suppress GC FSH-R expression, GC mitogen
       • Both thought to activate cumulus cell MAPK signalling, enabling GV breakdown and ovulation
       • Recombinant Bmp-15 in culture promoted GC proliferation and suppression of FSH-R expression

2. GDFs

   • Gdf-9
     • KO infertile, folliculogenesis arrested at one layer primary stage, suggests role as a GC mitogen
       • PARACRINE: Granulosa and theca growth and differentiation
       • AUTOCRINE: maturation of the oocyte
       • When recombinant Gdf-9 is given to the follicles in vitro, it promotes GC proliferation, suppression of the LH-R, and stimulation of both hyaluronan synthetase-2 and COX-2 required for COC expansion
     • Well-described oocyte-derived GFs, with synergistic actions promoting oocyte ovulation and somatic cell proliferation
       • In vitro, double mutants (het Gdf-9 and homo Bmp-15 null) oocytes can undergo stimulated GVB and promotion of M2 meiosis, but the fertilisation rate is reduced and 2-cell blastocyst development is retarded (Eppig lab, 2004)
         • Granulosa-Oocyte "regulatory loop"

3. AMH

   • Leydig cell hyperplasia and infertility (required for mullerian duct regression)
   • Premature "dissappearance" of primordial follicles in females - suggests a role in suppressing follicular activation
     • POF
   • Receptor expressed in Sertoli and granulosa cells
   • Molecular biomarker of ovarian reserve
     • Produced by the granulosa cells of growing follicles, and acts as a feedback mechanism to prevent the recruitment of too many primordial follicles

4. Mechanism of Action

   • Ligand Activation
     • They are secreted in their latent form, and become activated upon cleavage of the Latency Associated Protein (LAP), likely by endoprotease action, of under the action of ECM TSP-1 or integrin action
   • Ligand Binding to Transcellular Receptors
     • They bind to transmembrane serine/threonine kinase receptors
       • Further signalling occurs via the phosphorylation of particular SMAD proteins, of which now migrate to the nucleus and interact with transcription factors to stimulate specific genes
     • Ligand binding can be prevented by binding proteins (e.g. follistatin, which binds to activin

5. Inhibin

   • Closely related, with proposed opposite functions
   • Prevents the secretion of FSH from the pituitary (negative feedback)
     • produced in greatest amounts by the preovulatory follicles and CL
   • plays a similar inhibitory role as follistatin

6. Activin

   • enhances the biosynthesis of FSH in the pituitary

7. Structurally related cell regulatory proteins, largely involved in ovarian paracrine signalling