Enhanced at puberty 1 (EAP1) is a new transcriptional regulator of the female neuroendocrine reproductive axis

Abstract

The 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 lentivirusmediated 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.

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“…Furthermore, the repressive effect of DIF-1 is highly dependent on EAP1 and BP1 since knockdown of one or both factors reversed DIF-1-mediated repression. Consistent with these factors acting as a complex, DIF-1, BP1, and EAP1 colocalize in the nucleus in cell lines and coexpress in the specific regions of the hypothalamus where EAP1 was reported to exert its facilitatory effect on female reproductive function (14).…”

“…EAP1 has been implicated as a transcriptional regulator of female reproductive function through actions exerted in the preoptic region of the basal forebrain (14). Knockdown of EAP1 targeted to this region of the brain compromises both the timing of puberty and the cyclicity of female reproductive function.…”

“…Since EAP1 forms a complex with DIF-1 and BP1, and NRIF3 interacts with DIF-1, we sought to determine whether the mRNAs encoding these proteins are expressed in the same cells. Within the hypothalamus, EAP1 localizes to areas involved in reproductive control: the medial preoptic area, arcuate nucleus, and the ventromedial nucleus (14). Double hybridization histochemistry indicates that EAP1 mRNAcontaining neurons also express NRIF3, BP1, and DIF-1 mRNA (see Fig.…”

“…1B). In addition, GFP-DIF-1, GFP-BP1, and GFP-EAP1 each show a similar nuclear localization pattern with nucleoli exclusion when expressed in HeLa cells EAP1 was previously shown to be widely expressed in the brain (14). Since EAP1 forms a complex with DIF-1 and BP1, and NRIF3 interacts with DIF-1, we sought to determine whether the mRNAs encoding these proteins are expressed in the same cells.…”

“…BP1 has been reported to promote the activity of transforming growth factor ␤ (TGF␤) in cells (9). Thus far, the only physiological context in which EAP1 has been shown to participate is in the neuroendocrine control of female puberty and female reproductive cyclicity (14). Knockdown of EAP1 targeted to the preoptic region of the hypothalamus results in delayed puberty and disrupted estrous cyclicity.…”