IGSF1 Deficiency Leads to Reduced TSH Production Independent of Alterations in Thyroid Hormone Action in Male Mice

Abstract

Loss of function mutations in IGSF1/Igsf1 cause central hypothyroidism. Igsf1 knockout mice have reduced pituitary thyrotropin-releasing hormone receptor, Trhr, expression, perhaps contributing to the phenotype. As thyroid hormones negatively regulate Trhr, we hypothesized that IGSF1 might affect thyroid hormone availability in pituitary thyrotropes. Consistent with this idea, IGSF1 co-immunoprecipitated with the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) in transfected cells. This association was impaired with IGSF1 bearing patient-derived mutations. Wild-type IGSF1 did not, however, alter MCT8-mediated thyroid hormone import into heterologous cells. IGSF1 and MCT8 are both expressed in the apical membrane of the choroid plexus. However, MCT8 protein levels and localization in the choroid plexus were unaltered in Igsf1 knockout mice, ruling out a necessary chaperone function for IGSF1. MCT8 expression was low in the pituitary and was similarly unaffected in Igsf1 knockouts. We next assessed whether IGSF1 affects thyroid hormone transport or action, by MCT8 or otherwise, in vivo. To this end, we treated hypothyroid wild-type and Igsf1 knockout mice with exogenous thyroid hormones. T4 and T3 inhibited TSH release and regulated pituitary and forebrain gene expression similarly in both genotypes. Interestingly, pituitary TSH beta subunit (Tshb) expression was consistently reduced in Igsf1 knockouts relative to wild-type regardless of experimental condition, whereas Trhr was more variably affected. While IGSF1 and MCT8 can interact in heterologous cells, the physiological relevance of their association is not clear. Nevertheless, the results suggest that IGSF1 loss can impair TSH production independently of alterations in TRHR levels or thyroid hormone action.

Hypothalamic hormone deficiency enables physiological anorexia

“…The second step involves IGSF1, a protein expressed in squirrel hypothalamic neurons and astrocytes. IGSF1 dysfunction is strongly linked with congenital central hypothyroidism in humans, and this phenotype is recapitulated in mouse models [41][42][43][44][45] .…”

“…Next, we assessed the level of expression of the immunoglobulin superfamily member 1 (Igsf1). Loss of function mutations in IGSF1 causes central hypothyroidism in humans and mice [41][42][43][44][45] . Igsf1 was expressed in neurons and astrocytes of squirrel ARC, and the level of expression significantly decreased in both groups during IBA (Extended Data Fig.…”

The hypothalamic–pituitary–thyroid axis is intact in male Irs4 knockout mice

“…Our results are consistent with those of a previous report that similarly showed euthyroidism in another Irs4 knockout strain ( 3 ). We extended the analysis here to include mice challenged with a hypothyroid diet, as this can reveal phenotypes not apparent in mice under standard laboratory conditions ( 18 , 19 ). Here, too, however, TSH synthesis and secretion were intact.…”

“…TRH-stimulated TSH release is impaired in IGSF1-deficient humans and mice. The latter also exhibit reductions in pituitary Tshb and Trhr expression ( 5 , 18 , 19 ), though how IGSF1 loss produces these effects has not yet been determined.…”

“…chow low in iodine and supplemented with propylthiouracil) were not examined. From our experience with Igsf1 knockout mice, this challenge may be needed to reveal robust impairments in TSH synthesis and secretion ( 18 , 19 ). We therefore generated and characterized novel Irs4 knockout mouse strains to determine if or how IRS4 regulates TSH in vivo .…”