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Pulse Sensitivity of the Luteinizing Hormone ß Promoter Is Determined by a Negative Feedback Loop Involving Early Growth Response-1 and Ngfi-A Binding Protein 1 and 2

Departments of Reproductive Medicine (M.A.L., B.K.B., S.J.S., P.L.M.), Neuroscience (P.L.M.,), and Medicine (R.T., H.Z., I.T., N.J.G.W.), and the University of California San Diego Cancer Center (P.L.M., N.J.G.W.), University of California, San Diego, California 92093; and the Medical Research Service (N.J.G.W.), Veterans Affairs San Diego Healthcare System, San Diego, California 92161

Address all correspondence and requests for reprints to: Mark Lawson, Department of Reproductive Medicine 0674, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: mlawson{at}ucsd.edu.

The hypothalamic-pituitary-gonadal endocrine axis regulates reproduction through estrous phase-dependent release of the heterodimeric gonadotropic glycoprotein hormones, LH and FSH, from the gonadotropes of the anterior pituitary. Gonadotropin synthesis and release is dependent upon pulsatile stimulation by the hypothalamic neuropeptide GnRH. Alterations in pulse frequency and amplitude alter the relative levels of gonadotropin synthesis and release. The mechanism of interpretation of GnRH pulse frequency and amplitude by gonadotropes is not understood. We have examined gene expression in LßT2 gonadotropes under various pulse regimes in a cell perifusion system by microarray and identified 1127 genes activated by tonic or pulsatile GnRH. Distinct patterns of expression are associated with each pulse frequency, but the greatest changes occur at a 60-min or less interpulse interval. The immediate early gene mRNAs encoding early growth response (Egr)1 and Egr2, which activate the gonadotropin LH ß-subunit gene promoter, are stably induced at high pulse frequency. In contrast, mRNAs for the Egr corepressor genes Ngfi-A binding protein Nab1 and Nab2 are stably induced at low pulse frequency. We show that Ngfi-A binding protein members inhibit Egr-mediated frequency-dependent induction of the LH ß-subunit promoter. This pattern of expression suggests a model of pulse frequency detection that acts by suppressing activation by Egr family members at low frequency and allowing activation at sustained high-frequency pulses.

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