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Notes: The prototypic pineal hormone, melatonin reputedly exerts many functional effects on mammalian skin and/or its isolated cell populations in culture (e.g., melanogenesis inhibition, melanocyte growth inhibition, regulation of seasonal changes in the pelage), and is recognized as a potent free radical scavenger. In mammals, two types of high-affinity membrane melatonin receptors, MT1 and MT2 have been identified, which inhibit adenylate cyclase activity to decrease the intracellular level of cAMP. Low-affinity membrane receptor MT3/QR2 have also been identified, though the mechanism has not been cleared yet. Melatonin is also a natural ligand of nuclear transcription factor ROR(α and β), which is suggested to regulate cell cycle negatively via target gene such as p21WAF/CIP1. Due to its lipophilic structure, melatonin also enters through both the plasma and nuclear membrane, and acts as a potent free radical scavenger to protect macromolecules, in particular DNA. Melatonin demonstrates differential – and often still confusing seemingly contradictory– effects on cell activity in many different systems, which may be explained by this multitude of signaling pathways that are modulated by melatonin bioactivity. Recently, cultured epidermal and follicular melanocytes, keratinocytes, and fibroblasts, have also been found to display the enzymatic activity of arylalkylamine N-acetyltransferase and hydroxyindole -O- methyltransferase for melatonin synthesis. However, little is known about the cutaneous expression and regulation of melatonin and its receptors in situ, and the functional role of melatonin in normal skin and hair follicle biology is still obscure. In order to study whether murine hair follicles in situ are indeed direct peripheral melatonin targets, the follicular expression of MT1, MT2 and/or RORα are investigated. Immunohistochemistry revealed that C57BL/6 mouse hair follicle keratinocytes in situ show prominent MT1-like immunoreactivity (IR), which changed substantially in a hair cycle-dependent manner. RORα-like IR was also detected in murine hair follicles, and also displayed hair cycle dependence. RT-PCR of MT1 and MT2, and real time PCR for MT1, MT2 and RORα on C57BL/6 mice skin cDNA revealed that all three genes are transcribed in normal mouse skin, and demonstrated that their expression/transcription is hair cycle-dependent. In conclusion, normal murine hair follicles are indeed a prominent, direct target for melatonin bioregulation, through MT1, MT2 and RORα melatonin receptors and that at least some of these regulators are functionally active in situ. The observed hair cycle dependence of melatonin receptor expression suggests a role of melatonin in hair cycle control.