Abstract
Hypothalamic Kiss1 neurons control gonadotropin-releasing hormone release through the secretion of kisspeptin. Kiss1 neurons serve as a nodal center that conveys essential regulatory cues for the attainment and maintenance of reproductive function. Despite this critical role, the mechanisms that control kisspeptin synthesis and release remain largely unknown. Using Drop-Seq data from the arcuate nucleus of adult mice and in situ hybridization, we identified Nescient Helix-Loop-Helix 2 (Nhlh2), a transcription factor of the basic helix-loop-helix family, to be enriched in Kiss1 neurons. JASPAR analysis revealed several binding sites for NHLH2 in the Kiss1 and Tac2 (neurokinin B) 5' regulatory regions. In vitro luciferase assays evidenced a robust stimulatory action of NHLH2 on human KISS1 and TAC3 promoters. The recruitment of NHLH2 to the KISS1 and TAC3 promoters was further confirmed through chromatin immunoprecipitation. In vivo conditional ablation of Nhlh2 from Kiss1 neurons using Kiss1Cre:Nhlh2fl/fl mice induced a male-specific delay in puberty onset, in line with a decrease in arcuate Kiss1 expression. Females retained normal reproductive function albeit with irregular estrous cycles. Further analysis of male Kiss1Cre:Nhlh2fl/fl mice revealed higher susceptibility to metabolic challenges in the release of luteinizing hormone and impaired response to leptin. Overall, in Kiss1 neurons, Nhlh2 contributes to the metabolic regulation of kisspeptin and NKB synthesis and release, with implications for the timing of puberty onset and regulation of fertility in male mice.
Highlights
Hypothalamic Kiss1 neurons secrete kisspeptins (Pinilla et al, 2012), which act directly on gonadotropin-releasing hormone (GnRH) neurons (Irwig et al, 2004) to stimulate GnRH release
Nescient HelixLoop-Helix 2 (Nhlh2) is highly expressed in Kiss1 neurons from the time of their initial development during the embryonic phase (Huisman et al, 2019), and our data indicate that this co-expression is retained into adulthood
We demonstrate that Nhlh2 potently enhances the activity of KISS1 and TAC3 promoters, suggesting a potential role in the central activation of the reproductive axis by controlling kisspeptin output
Summary
Hypothalamic Kiss neurons secrete kisspeptins (Pinilla et al, 2012), which act directly on gonadotropin-releasing hormone (GnRH) neurons (Irwig et al, 2004) to stimulate GnRH release. Pulsatile GnRH release increases at the end of the juvenile period, determining the onset of puberty and the transition into adulthood (Ojeda et al, 2010). This process is largely dependent on the activation of Kiss neurons, in part, through the autosynaptic excitatory action of neurokinin B (NKB) (Garcia et al, 2017; Gill et al, 2012; Navarro et al, 2012a; Ruiz-Pino et al, 2012) and the inhibitory action of dynorphin through an autosynaptic alternation process that creates the
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