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Divergent roles of growth factors in the GnRH regulation of puberty in mice
Sara A. DiVall, … , Sally Radovick, Andrew Wolfe
Sara A. DiVall, … , Sally Radovick, Andrew Wolfe
Published July 12, 2010
Citation Information: J Clin Invest. 2010;120(8):2900-2909. https://doi.org/10.1172/JCI41069.
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Research Article Endocrinology

Divergent roles of growth factors in the GnRH regulation of puberty in mice

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Abstract

Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states.

Authors

Sara A. DiVall, Tameeka R. Williams, Sarah E. Carver, Linda Koch, Jens C. Brüning, C. Ronald Kahn, Fredric Wondisford, Sally Radovick, Andrew Wolfe

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Figure 2

GnRH-IRKO mice have normal onset of puberty and reproductive function.

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GnRH-IRKO mice have normal onset of puberty and reproductive function.
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(A) Pubertal evaluation included the time of vaginal opening and first estrus in control (n = 8) and GnRH-IRKO (n = 8) females and balanopreputial separation in control (n = 6) and GnRH-IRKO (n = 6) males. (B) AGD, which is testosterone dependent, was also assessed in males of pubertal age (n = 4 each group). (C) Body weight of pubertal animals (n = 5 each group). Vaginal cytology for at least 14 consecutive days was performed in 4 female mice of each genotype to evaluate estrous cycling. (D) Estrous cycle length. (E) Time in each estrous cycle phase. P, proestrus; E, estrus; M/D, metestrus/diestrus. (F) To assess fertility, we determined the time to birth after introduction with a male and the number of pups per litter. (G) Serum LH was determined in 5 adult mice of each sex and genotype. Values are mean ± SEM.

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