Addition of a carboxy terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice

Toufaily, C.; Fortin, J.; Alonso, C. A. I.; Lapointe, E.; Zhou, X.; Santiago-Andres, Y.; Lin, Y.-F.; Cui, Y.; Wang, Y.; Devost, D.; Roelfsema, F.; Steyn, F.; Hanyaloglu, A. C.; Hebert, T.; Fiordelisio, T.; Boerboom, D.; Bernard, D. J.

doi:10.1101/2021.09.13.460073

bioRxiv · 10.1101/2021.09.13.460073

Addition of a carboxy terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice

Toufaily, C.·Fortin, J.·Alonso, C. A. I.·Lapointe, E.·Zhou, X.·Santiago-Andres, Y.·Lin, Y.-F.·Cui, Y.·Wang, Y.·Devost, D.·Roelfsema, F.·Steyn, F.·Hanyaloglu, A. C.·Hebert, T.·Fiordelisio, T.·Boerboom, D.·Bernard, D. J.

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Abstract

Gonadotropin-releasing hormone (GnRH) is the primary neuropeptide controlling reproduction in vertebrates. GnRH stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis via a G protein-coupled receptor, GnRHR, in the pituitary gland. In mammals, GnRHR lacks a C-terminal cytosolic tail (Ctail) and does not exhibit homologous desensitization. This might be an evolutionary adaptation that enables LH surge generation and ovulation. To test this idea, we fused the chicken GnRHR Ctail to the endogenous murine GnRHR in a transgenic model. The LH surge was blunted, but not blocked in these mice. In contrast, they showed reductions in FSH production, ovarian follicle development, and fertility. Addition of the Ctail altered the nature of agonist-induced calcium signaling required for normal FSH production. The loss of the GnRHR Ctail during mammalian evolution is unlikely to have conferred a selective advantage by enabling the LH surge. The adaptive significance of this specialization remains to be determined.

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Toufaily, C., Fortin, J., Alonso, C. A. I., Lapointe, E., Zhou, X., Santiago-Andres, Y., Lin, Y.-F., Cui, Y., Wang, Y., Devost, D., Roelfsema, F., Steyn, F., Hanyaloglu, A. C., Hebert, T., Fiordelisio, T., Boerboom, D., Bernard, D. J.. 2021-09-16. Addition of a carboxy terminal tail to the normally tailless gonadotropin-releasing hormone receptor impairs fertility in female mice. https://doi.org/10.1101/2021.09.13.460073

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