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Male-Biased Effects of Gonadotropin-Releasing Hormone Neuron-Specific Deletion of the Phosphoinositide 3-Kinase Regulatory Subunit p85 on the Reproductive Axis

Department of Neurobiology and Physiology (M.A.-M., J.E.L.), Northwestern University, Evanston, Illinois 60202; Department of Genetics (J.L.), Harvard Medical School, and Department of Medicine (J.L.), Brigham and Women’s Hospital, Boston, Massachusetts 02115; Division of Hypothalamic Research (C.E.), Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9077; and Department of Pediatrics (A.W.), Johns Hopkins School of Medicine, Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Jon E. Levine, Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: jlevine{at}northwestern.edu.

GnRH neurosecretion is subject to regulation by insulin, IGF-I, leptin, and other neuroendocrine modulators whose effects may be conveyed by activation of phosphoinositide 3-kinase (PI3K)-mediated pathways. It is not known, however, whether any of these regulatory actions are exerted directly, via activation of PI3K in GnRH neurons, or whether they are primarily conveyed via effects on afferent circuitries governing GnRH neurosecretion. To investigate the role of PI3K signaling in GnRH neurons, we used conditional gene targeting to ablate expression of the major PI3K regulatory subunit, p85, in GnRH neurons. Combined in situ hybridization and immunohistochemistry confirmed reduction of p85 mRNA expression in GnRH neurons of GnRH-p85 knockout (KO) animals. Females of both genotypes exhibited estrous cyclicity and had comparable serum LH, estradiol-17β, and FSH levels. In male GnRH-p85KO mice, serum LH, testosterone, and sperm counts were significantly reduced compared with wild type. To investigate the role of the other major regulatory subunit, p85β, on the direct control of GnRH neuronal function, we generated mice with a GnRH-neuron-specific p85 deletion on a global βKO background. No additional reproductive effects in male or female mice were found, suggesting that p85β does not substitute p85 activity toward PI3K function in GnRH neurons. Our results suggest that p85, and thus PI3K activity, participates in the control of GnRH neuronal activity in male mice. The sex-specific phenotype in these mice raises the possibility that PI3K activation during early development may establish sex differences in GnRH neuronal function.