Best Practice & Research Clinical Endocrinology & Metabolism
1Mouse models for the analysis of gonadotropin secretion and action
Introduction
The anterior pituitary is composed of five cell types-gonadotropes, thyrotropes, somatotropes, lactotropes, and corticotropes. The gonadotropes produce luteinizing hormone (LH) and follicle stimulating hormone (FSH), and the thyrotropes produce thyroid stimulating hormone (TSH). LH, FSH, and TSH belong to the pituitary glycoprotein family of heterodimeric hormones consisting of a common α-subunit non-covalently linked to a hormone-specific β-subunit [1]. Human chorionic gonadotropin (hCG) shares the same α-subunit as LH, FSH, and TSH, but the hCG heterodimer is derived from placental syncytiotrophoblast cells [2]. While hCG is only found in primates and horses, the pituitary gonadotropins are conserved throughout mammalian evolution and will be the focus of this review ∗[1], [3].
The gonadotropin α- and β-subunits are encoded by distinct single-copy genes located on separate chromosomes. In humans, the α-subunit is mapped to chromosome 6, the LHβ-subunit is mapped to chromosome 19, and the FSHβ-subunit is mapped to chromosome 11 ∗[1], [4]. LH and FSH are under transcriptional and translational control by multiple factors including the downstream sex steroids, and the upstream signal from the hypothalamic derived decapeptide, gonadotropin-releasing hormone (GnRH) [5], [6], [7]. Pituitary-specific cell fate and function appears to be under partial control of the GATA family of transcription factors which are present at high levels in the developing pituitary and adult gonadotropes [8]. Although LH and FSH are released from the same cell, they are secreted independently of each another, and their secretion is distinctly regulated by GnRH pulsatility and differences in segregation into secretory granules ∗[1], [6], [9].
LH acts on target cells by binding to the LH receptor (LHR), and is required for steroidogenesis, gonadal growth, and gametogenesis. LHR is expressed on testicular Leydig cells as well as ovarian granulosa and theca cells. FSH signals via the FSH receptor (FSHR), and is essential for initiation of spermatogenesis and follicle maturation in males and females, respectively. FSHR is expressed on ovarian granulosa cells and on Sertoli cells in the testes. Recent reports have identified expression of FSHR in several extra-gonadal tissues, including uterus, placenta, adipose tissue, bone, and tumor blood vessels [10]. In this review, we will focus primarily on mouse models that were developed to study LH and FSH actions at the level of the ovary and testis. We will also review known actions of FSH on bone and adipose tissue, as these tissues in mouse models have recently been highlighted in the field of gonadotropin action (Fig. 1).
Section snippets
α-Glycoprotein subunit overexpression
The common α-subunit (Cga) mRNA is present as early as embryonic day 11.5 (E11.5) in the mouse pituitary [11]. It is the first of the glycoprotein hormone subunits to be expressed during development, and it is synthesized in excess compared to β-subunit transcripts [3]. In 1988, using a transgenic mouse model overexpressing human CGA, Fox and Solter demonstrated that the human transgene is only expressed in the pituitary in mice demonstrating that mouse trophoblast cells lack the regulatory
Summary
Both gain of function and loss of function mouse models were generated to understand gonadotropin action in a physiological context. In many cases, the mouse models closely phenocopy human mutations (Table 1) and thus these models provide useful tools to developmentally track the phenotypes over longer periods of time. In some instances, genetic rescue of mutant mice lacking a single gonadotropin has also been achieved by combining the loss of function and gain of function mouse models. Loss of
Disclosure statement
The authors have nothing to disclose.
Acknowledgments
Financial support from the NIH Loan Repayment program (to S.B.G.) and in part from the NIH grants CA166557, AG029531, AG056046, HD081162 and The Makowski Endowment (to T.R.K.) are acknowledged.
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These authors contributed equally.