title: Hypothalamic EAP1 (enhanced at puberty 1) is required for menstrual cyclicity in nonhuman primates.
abstract: Mammalian reproductive cyclicity requires the periodic discharge of GnRH from hypothalamic neurons into the portal vessels connecting the neuroendocrine brain to the pituitary gland. GnRH secretion is, in turn, controlled by changes in neuronal and glial inputs to GnRH-producing neurons. The transcriptional control of this process is not well understood, but it appears to involve several genes. One of them, termed enhanced at puberty 1 (EAP1), has been postulated to function in the female hypothalamus as an upstream regulator of neuroendocrine reproductive function. RNA interference-mediated inhibition of EAP1 expression, targeted to the preoptic region, delays puberty and disrupts estrous cyclicity in rodents, suggesting that EAP1 is required for the normalcy of these events. Here, we show that knocking down EAP1 expression in a region of the medial basal hypothalamus that includes the arcuate nucleus, via lentiviral-mediated delivery of RNA interference, results in cessation of menstrual cyclicity in female rhesus monkeys undergoing regular menstrual cycles. Neither lentiviruses encoding an unrelated small interfering RNA nor the placement of viral particles carrying EAP1 small interfering RNA outside the medial basal hypothalamus-arcuate nucleus region affected menstrual cycles, indicating that region-specific expression of EAP1 in the hypothalamus is required for menstrual cyclicity in higher primates. The cellular mechanism by which EAP1 exerts this function is unknown, but the recent finding that EAP1 is an integral component of a powerful transcriptional-repressive complex suggests that EAP1 may control reproductive cyclicity by inhibiting downstream repressor genes involved in the neuroendocrine control of reproductive function.
authors: Division of Neuroscience, Oregon National Primate Research Center, 505 North West 185th Avenue, Beaverton, Oregon 97006-3448, USA. disseng@ohsu.edu
authors: Gregory A
authors: GA
authors: Dissen
authors: Alejandro
authors: A
authors: Lomniczi
authors: Sabine
authors: S
authors: Heger
authors: Tanaya L
authors: TL
authors: Neff
authors: Sergio R
authors: SR
authors: Ojeda
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D015870:Gene Expression; D007031:Hypothalamus / Q000033:anatomy & histology / Q000502:physiology*; D066298:In Vitro Techniques; D008253:Macaca mulatta / Q000033:anatomy & histology / Q000235:genetics* / Q000502:physiology*; D008597:Menstrual Cycle / Q000235:genetics* / Q000502:physiology*; D009490:Neurosecretory Systems / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D034741:RNA, Small Interfering