Figure 5: Proposed model for IGSF1 functions and molecular mechanisms involved in IGSF1 deficiency.

(A) In thyrotropes, TGFβ1 activates TGFβ receptors (TBRs) and stimulates Smad2/3 signaling cascade leading to repression of the TRHR gene, which reduces the TRH-TRHR signaling over the TSHB expression. IGSF1 (green symbols) represses TGFβ1 pathway, positively regulating TRHR expression and therefore enhancing TRH-TRHR signaling, TSHB synthesis and bioactivity (glycosylation) and TSH secretion from the pituitary. In the thyroid, TSH stimulates the TSHR and the synthesis of thyroid hormones (T4, T3) which exert a negative feedback over TSHB expression at the pituitary. IGSF1 deficiency (red symbols) reduces TSH synthesis and bioactivity, leading to central hypothyroidism. (B) In gonadotropes, activin A binds activin receptors (ActRs) and stimulates Smad2/3 pathway to increase FSHB transcription. FSH stimulates FSHR of Sertoli cells in testis, producing inhibin B, which exerts negative feedback over pituitary FSHB expression. IGSF1 (green symbols) inhibits activin A pathway, negatively regulating FSHB expression. IGSF1 is proposed here as a mediator of inhibin B-repressive effects on FSHB production (black double-arrow). IGSF1 deficiency (red symbols) leads to over-secretion of pituitary FSH, inducing proliferation of Sertoli cell mass (macroorchidism) and excess synthesis of Inhibin B which, however, seems unable to exert the negative feed-back over the synthesis of FSH at the pituitary, representing a state of resistance to Inhibin B. TRH: thyrotropin-releasing hormone, GnRH: gonadotropin-releasing hormone, TGFβ1: Transforming Growth Factor beta 1 protein, TBRs: TGFβ1 receptors, TRHR: thyrotropin-releasing hormone receptor, TSHB: thyrotropin beta subunit gene, TSHR: thyrotropin receptor, T4: thyroxine, T3: triiodothyronine, ActR: activin A receptors, FSHB: follicle-stimulating hormone beta, FSH: follicle-stimulating hormone, FSHR: follicle-stimulating hormone receptor.