Spatial and temporal expression of immunoglobulin superfamily member 1 in the rat

Abstract

Loss-of-function mutations in the immunoglobulin superfamily member 1 (IGSF1) gene cause an X-linked syndrome of central hypothyroidism, macroorchidism, variable prolactin and GH deficiency, delayed pubertal testosterone rise, and obesity. To understand the pathophysiology of this syndrome, knowledge on IGSF1's place in normal development is imperative. Therefore, we investigated spatial and temporal protein and mRNA expression of IGSF1 in rats using immunohistochemistry, real-time quantitative PCR (qPCR), and in situ hybridization. We observed high levels of IGSF1 expression in the brain, specifically the embryonic and adult choroid plexus and hypothalamus (principally in glial cells), and in the pituitary gland (PIT1-lineage of GH, TSH, and PRL-producing cells). IGSF1 is also expressed in the embryonic and adult zona glomerulosa of the adrenal gland, islets of Langerhans of the pancreas, and costameres of the heart and skeletal muscle. IGSF1 is highly expressed in fetal liver, but is absent shortly after birth. In the adult testis, IGSF1 is present in Sertoli cells (epithelial stages XIII-VI), and elongating spermatids (stages X-XII). Specificity of protein expression was corroborated with Igsf1 mRNA expression in all tissues. The expression patterns of IGSF1 in the pituitary gland and testis are consistent with the pituitary hormone deficiencies and macroorchidism observed in patients with IGSF1 deficiency. The expression in the brain, adrenal gland, pancreas, liver, and muscle suggest IGSF1's function in endocrine physiology might be more extensive than previously considered.

The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFβ and Activin pathways

“…Our results fully agree with initial reports using double immunohistochemistry and an IGSF1 antibody made in house on the presence of Igsf1 in adult rat FSH beta +ve cells7. In contrast, reports in adult rat pituitary22 and mouse embryo4, both using an antibody made against aa 559–575 of IGSF1 showed staining in Pit-1 +ve cells and not in gonadotropes. We can only speculate about the reasons for these differences.…”

“…This suggests that the testicular phenotype is not due to primary failure of testicular IGSF14954 but to overstimulation of Sertoli cells by pituitary FSH (main known stimulus for Inhibin/AMH secretion and Sertoli cell proliferation). Other researchers also found IGSF1 protein and mRNA in mouse germinal epithelium, (less) in Leydig cells and also in Sertoli cells, but only at stages VI–XIII of the maturating tubular epithelium22. Our human and mouse testis tissues seem to contain seminiferous tubules full of mature spermatozoids and, in those stages, our study coincides with Joustra’s in finding Sertoli cells negative for IGSF1.…”

“…We identified here a mechanism whereby IGSF1 deficiency down-regulates endogenous TRHR, a pivotal molecule at the crossroad of TSH secretion signaling. Notwithstanding, Igsf1 mRNA was recently detected in the rat hypothalamus, mainly in glial cells (Gfap positive), but also in a small subset of TRH neurons22. Therefore, we cannot exclude other roles for IGSF1 at the hypothalamus that could also contribute to the phenotype of our patient.…”

“…These results are in contrast with previous results by Joustra et al . using a different antibody that localized Igsf1 in Pit-1 expressing cells within the rat pituitary, while SF-1/Lh expressing cells did not co-localize with Igsf122.…”

The short mRNA isoform of the immunoglobulin superfamily, member 1 gene encodes an intracellular glycoprotein

“…IGSF1 is abundantly expressed in the developing and adult pituitary gland [3–5]. According to observations in both humans and mice, IGSF1-deficiency is associated with impaired hypothalamic thyrotropin-releasing hormone (TRH) stimulation of thyroid-stimulating hormone (TSH) synthesis and/or secretion by thyrotrope cells of the anterior pituitary [2, 3, 6, 7].…”