In vivo consequences of the expression of constitutively active luteinizing hormone receptors
Meehan, Thomas Paul
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Luteinizing hormone (LH) is critical for reproduction in mammals. Its activity is delineated through the signaling of a member of the G-protein coupled receptor superfamily, the luteinizing hormone receptor (LHR), which LH shares with the very closely related hormone, human chorionic gonadotropin (hCG). Constitutively activating mutations in LHR occur in cases of sporadic and familial male-limited precocious puberty, a disorder characterized by prepubertal testosterone synthesis and Leydig cell hyperplasia. Additionally, a somatic mutation in LHR, D578H, has been described in the Leydig cell adenomas of boys presenting with precocious puberty. In order to establish an in vivo model for chronic LHR activation, transgenic mice were generated utilizing two constitutively active receptors, a D556H rat LHR (equivalent to D578H in human LHR) and a yoked hormone receptor complex (YHR), in which the heterodimeric hormone hCG is fused and then covalently attached to the N-terminus of rat LHR. These receptors were cloned under the control of the mouse inhibin á -subunit promoter to target expression to the gonads of transgenic mice. D556H rLHR founder mice were infertile while several lines were established from YHR founders. In male mice, expression of YHR causes premature testosterone production and seminal vesicle development, as well as impaired testicular development. Female mice undergo precocious puberty resulting from an increase in steroid hormone production and increased folliculogenesis, as well as premature ovarian aging characterized by follicular cysts and interstitial cell hyperplasia and luteinization. In addition to the transgenic mouse model, a tetracycline-regulated system was established to control the expression of YHR, which was shown to be under tight control for the dose and time of doxycycline exposure.