Reproductive Physiology of a Humanized GnRH Receptor Mouse Model: Application in Evaluation of Human-Specific Analogues

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 134-163-GnRH & Gonadotroph Biology & Signaling
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-161
Javier A Tello*1, Trudy Ana Kohout2, Rafael Pineda1, Scott Struthers3 and Robert Peter Millar4
1University of Edinburgh, Edinburgh, United Kingdom, 2Neurocrine Biosci Inc, Solana Beach, CA, 3Crinetics Pharmaceuticals Inc., San Diego, CA, 4Mammal Research Institute, Pretoria 0002, South Africa
The human GNRH receptor (GNRHR1) has a specific set of properties amongst GnRH receptors that influence physiology and pharmacology, which are not appropriately modeled in laboratory animals or cell based systems. To address this deficiency we have generated human GNRHR1 knock-in mice and describe their reproductive phenotype. Measurement of pituitary GNRHR1 transcripts from homozygous human GNRHR1 knock-in mice revealed a severe reduction (7 to 8-fold) compared to the mouse Gnrhr1 in wild type mice. 125I-GnRH binding assays on pituitary membrane fractions corroborated reduced human GNRHR protein expression in knock-in mice, as occurs with transfection of human GNRH receptors in cell lines. Female homozygous knock-in mice displayed normal pubertal onset indicating that a large reduction in GNRHR1 expression is sufficient for this process. However, knock-in females exhibited periods of prolonged estrous and/or metestrous and reduced fertility. No impairment was found in reproductive maturity or adult fertility in male knock-in mice. Interestingly, the serum LH response to GnRH challenge was reduced in both knock-in males and females, indicating a reduced GNRHR signaling capacity. Small molecules targeting human GPCRs usually have poor activities at homologous rodent receptors thus limiting their use in preclinical development. We therefore tested a human-specific GnRH antagonist, NBI-42902, in our mouse model and demonstrated abrogation of a GnRH-induced serum LH rise in knock-in mice and an absence of effect in littermates expressing the wild type murine receptor. This novel model provides the opportunity to study the human receptor in vivo and for screening the activity of human-specific GnRH analogues.

Nothing to Disclose: JAT, TAK, RP, SS, RPM

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