National Brain Research Program(2017-1.2.1-NKP-2017-00002)
Subjects:
Veterinary science
Kisspeptin neurons in the mediobasal hypothalamus (MBH) are critical targets of ovarian
estrogen feedback regulating mammalian fertility. To reveal molecular mechanisms underlying
this signaling, we thoroughly characterized the estrogen-regulated transcriptome of
kisspeptin cells from ovariectomized transgenic mice substituted with 17β-estradiol
or vehicle. MBH kisspeptin neurons were harvested using laser-capture microdissection,
pooled, and subjected to RNA sequencing. Estrogen treatment significantly (p.adj.
< 0.05) up-regulated 1,190 and down-regulated 1,139 transcripts, including transcription
factors, neuropeptides, ribosomal and mitochondrial proteins, ion channels, transporters,
receptors, and regulatory RNAs. Reduced expression of the excitatory serotonin receptor-4
transcript (Htr4) diminished kisspeptin neuron responsiveness to serotonergic stimulation.
Many estrogen-regulated transcripts have been implicated in puberty/fertility disorders.
Patients (n = 337) with congenital hypogonadotropic hypogonadism (CHH) showed enrichment
of rare variants in putative CHH-candidate genes (e.g., LRP1B, CACNA1G, FNDC3A). Comprehensive
characterization of the estrogen-dependent kisspeptin neuron transcriptome sheds light
on the molecular mechanisms of ovary–brain communication and informs genetic research
on human fertility disorders.
