Gene Expression in Mouse Thyrotrope Adenoma: Transcription Elongation Factor Stimulates Proliferation

Abstract

Thyrotrope hyperplasia and hypertrophy are common responses to primary hypothyroidism. To understand the genetic regulation of these processes, we studied gene expression changes in the pituitaries of Cga(-/-) mice, which are deficient in the common α-subunit of TSH, LH, and FSH. These mice have thyrotrope hypertrophy and hyperplasia and develop thyrotrope adenoma. We report that cell proliferation is increased, but the expression of most stem cell markers is unchanged. The α-subunit is required for secretion of the glycoprotein hormone β-subunits, and mutants exhibit elevated expression of many genes involved in the unfolded protein response, consistent with dilation and stress of the endoplasmic reticulum. Mutants have elevated expression of transcription factors that are important in thyrotrope function, such as Gata2 and Islet 1, and those that stimulate proliferation, including Nupr1, E2f1, and Etv5. We characterized the expression and function of a novel, overexpressed gene, transcription elongation factor A (SII)-like 5 (Tceal5). Stable expression of Tceal5 in a pituitary progenitor cell line is sufficient to increase cell proliferation. Thus, Tceal5 may act as a proto-oncogene. This study provides a rich resource for comparing pituitary transcriptomes and an analysis of gene expression networks.

S100a4-Cre–mediated deletion of Ptch1 causes hypogonadotropic hypogonadism: role of pituitary hematopoietic cells in endocrine regulation

“…The α subunit of glycoprotein hormones is required for the biosynthesis of LH, FSH, and TSH. In S100a4-Cre;Ptch1 fl/fl mutant mice, TSHβ (Tshb) mRNA levels were elevated in both sexes, consistent with previous studies where Tshb mRNA levels were elevated in Cga-knockout mice (29). Also consistent with data from the ovariectomy experiment described above, the levels of mRNA for Fshb was normal in the mutant females, whereas Lhb in the mutant females, as well as Lhb and Fshb in the mutant males, all had reduced mRNA levels.…”

“…We employed transmission electron microscopy (TEM) to further understand how different endocrine cell types in the pituitary were affected in these mutant mice ( Figure 6D). While gonadotropes appeared normal in the mutants of both sexes, thyrotropes in both male and female mutants displayed extensive expansion of dilated endoplasmic reticulum (ER), which was also observed in Cga-knockout mice and suggests ER stress (29). Secretory granules in thyrotropes distributed evenly across the cytoplasm in the control mice, but clustered near the cytoplasmic membrane in the mutant mice, suggesting abnormal production of TSH.…”

Liganded T3 receptor β2 inhibits the positive feedback autoregulation of the gene for GATA2, a transcription factor critical for thyrotropin production

“…As illustrated in Fig 7, we demonstrated here that liganded TRβ2 not only directly inhibits the promoters of the TSHβ and CGA genes [17,18] but also interferes with the GATA2 promoter. In agreement with our findings, two independent studies reported that GATA2 mRNA expression was increased in the pituitary gland of hypothyroid mice [58,59]. As shown in Fig 3, the liganded TRβ2 appears to function as a classical transcriptional repressor [49].…”

Identification of pituitary thyrotrope signature genes and regulatory elements

“…It is possible thyrotropes use a similar mechanism of increasing translation to meet the demand for thyrotropin. Consistent with this, Creb3l1 is upregulated in a model of thyrotrope adenoma (Gergics et al 2016).…”