SAT-416 IGSF1 Does Not Regulate FSH Synthesis or Secretion

Abstract

Loss of function mutations in the human X-linked immunoglobulin superfamily, member 1 (IGSF1) gene result in central hypothyroidism, often associated with macroorchidism. Igsf1-deficient mice are also centrally hypothyroid due to impaired TRH action in the pituitary. The mechanisms underlying macroorchidism are unclear and disputed. IGSF1 was originally characterized as an inhibin B co-receptor. As inhibin B negatively regulates FSH secretion, it was hypothesized that loss of IGSF1 would impair inhibin B action, leading to elevated FSH levels and enhanced Sertoli cell proliferation during development. Yet, in direct contradiction to this model, IGSF1 does not bind inhibin A or B in heterologous binding assays. Our preliminary data further indicate that FSHβ subunit (Fshb) mRNA expression is similarly antagonized by inhibin A and B in pituitary cultures from wild-type and Igsf1-deficient mice. More recently, IGSF1 was proposed to inhibit activin type IB receptor (ALK4) signaling. As activins stimulate FSH, loss of this inhibition should lead to increased FSH. However, neither humans nor mice with IGSF1-deficiency have elevated FSH and IGSF1 expression in FSH-producing gonadotrope cells is negligible. Additionally, Igsf1-deficient mice have normal serum LH and inhibin B levels, as well as testicular weights, histology, and semen parameters. Previous methods used to demonstrate IGSF1 regulation of a human FSHB promoter-reporter were conducted in a heterologous system in which such reporters lack activin/ALK4-dependent activity. We demonstrate that overexpression of IGSF1 in homologous LβT2 gonadotrope-like cells does not impair induction of murine or human Fshb/FSHB promoter-reporters by activin A or a constitutively active form of ALK4. Collectively, the available data fail to support a role for IGSF1 in FSH regulation by activins, inhibins, or otherwise.