Heger, SabineMastronardi, ClaudioDissen, Gregory A.Lomniczi, AlejandroCabrera, RicardoRoth, Christian L.Jung, HeikeGalimi, FrancescoSippell, WolfgangOjeda, Sergio R.2015-12-042015-12-040021-9738http://hdl.handle.net/1885/17024The initiation of mammalian puberty and the maintenance of female reproductive cycles are events controlled by hypothalamic neurons that secrete the decapeptide gonadotropin-releasing hormone (GnRH). GnRH secretion is, in turn, controlled by changes in neuronal and glial inputs to GnRH-producing neurons. The hierarchical control of the process is unknown, but it requires coordinated regulation of these cell-cell interactions. Here we report the functional characterization of a gene (termed enhanced at puberty 1 [EAP1]) that appears to act as an upstream transcriptional regulator of neuronal networks controlling female reproductive function. EAP1 expression increased selectively at puberty in both the nonhuman primate and rodent hypothalamus. EAP1 encoded a nuclear protein expressed in neurons involved in the inhibitory and facilitatory control of reproduction. EAP1 transactivated genes required for reproductive function, such as GNRH1, and repressed inhibitory genes, such as preproenkephalin. It contained a RING finger domain of the C3HC4 subclass required for this dual transcriptional activity. Inhibition of EAP1 expression, targeted to the rodent hypothalamus via lentivirus-mediated delivery of EAP1 siRNAs, delayed puberty, disrupted estrous cyclicity, and resulted in ovarian abnormalities. These results suggest that EAP1 is a transcriptional regulator that, acting within the neuroendocrine brain, contributes to controlling female reproductive function.This work was supported by grants from the NIH, the National Institute of Child Health and Human Development/NIH (to S.R. Ojeda), the European Society for Paediatric Endocrinology (to H. Jung), the German Research Foundation (to S. Heger), and the European Commission (PIONEER to S. Heger).Copyright © 2015 American Society for Clinical Investigation. http://www.sherpa.ac.uk/romeo/issn/0021-9738/..."Publishers version/PDF may be used on author's personal website, institutional website or institutional repository" from SHERPA/RoMEO site (as at 04/12/2015). This article may be downloaded for personal use only. Any other use requires prior permission of the author and American Society for Clinical Investigation.animalscarrier proteinsdown-regulationestrous cyclefemalegonadotropin-releasing hormonehumanshypothalamo-hypophyseal systemlentivirusmacaca mulattaneoplasm proteinsneuroglianeuronsnuclear proteinsovaryprotein precursorsprotein structure, tertiaryratsrats, sprague-dawleysecurintranscription factorstransduction, geneticsexual maturation2007-08-0110.1172/JCI317522015-12-08