Melatonergic Systems of AANAT, Melatonin, and Its Receptor MT2 in the Corpus Luteum Are Essential for Reproductive Success in Mammals†

Corpus luteum (CL) plays a critical role in mammalian reproductive physiology. Its dysfunction will lead to infertility or habitual abortion. In the current study, by use of melatonin specific membrane receptor 2 (MT2) knocking out (KO) mice model combined with RNA-Seq, immunohistochemistry, and immunofluorescence analyses, the genes of melatonin synthetic enzyme arylalkylamine N-acetyltransferase (AANAT) and MT2 were identified to strongly express in the CL of sows and mice. KO MT2 significantly impaired the reproductive performance in mice indicated by the reduced litter sizes. Melatonin treatment elevated the progesterone production in sows suggesting the improved CL function. Mechanistic analysis showed that melatonin upregulated a set of progesterone synthesis-related genes including cytochrome P450 family 11 subfamily A member 1 (Cyp11a1), aldo-keto reductase family 1, member C18 (Akr1c18), isopentenyl-diphosphate delta isomerase 1 (Idi1), and luteinizing hormone/choriogonadotropin receptor (Lhcgr). The upregulation of these genes directly related to the increased progesterone production. The regulatory effects of melatonin on these gene expressions were mediated by MT2 and MT2KO diminished the effects of melatonin in this respect. Thus, the presence of melatonergic system of AANAT, melatonin, and its receptor MT2 in CL is essential for reproductive success in mammals.