Analysis of the mutant mice for transcription factor Mitf, which exhibit abnormalities of respiratory control and circadian rhythm

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Differentiation of melanocytes is required for transcription factors MITF, SOX10, secretory protein Endothelin 3 and its receptor, Endothelin receptor type B (EDNRB). These mutant mice exhibit white coat color due to the lack of melanocytes.To search new physiological roles of melanocytes, we performed physiological analyses of the mitf mutant mouse, black-eyed white Mitf^<mi-bw> (bw). We thus found that bw mouse shows the increase of spontaneous behavior during the night compared with wild-type mouse. We further examined the breathing response of bw mouse, such as breathing frequency, tidal volume, and minute ventilation in unanesthetized and unrestrained mice by whole body plethysmography. The bw mouse exhibited the enhanced ventilatory responses to either hypoxia (10% O_2) or hypercapnia (10% CO_2). These unexpected findings suggest the abnormalities of circadian rhythm and respiratory regulation in bw mouse.To clarify the pathology of bw mouse, we compared mRNA expression profiles … More between wild type and homozygous bw mouse skin by cDNA microarray analysis, and identified lipocalin-type prostaglandin D synthase (L-PGDS) as a new melanocyte marker, which is responsible for prostaglandin D_2 production. MITF activates the transcription of the mouse L-PGDS gene, and may modulate the production of prostaglandin D_2 in melanocytes for the homeostasis in the skin.We also provide evidence that SOX10 regulates the expression of EDNRB gene in human melanocyte-lineage cells. Furthermore, we have shown that the EDNRB promoter is heavily methylated in HeLa human cervical cancer cells, lacking EDNRB expression, but not in melanocyte-lineage cells. The expression of EDNRB became detectable in HeLa cells after treatment with a demethylating reagent, 5'-aza-2'-deoxycytidine, which was further enhanced in the transformed cells over-expressing SOX10. These results suggest that SOX10 regulates transcription of the EDNRB gene, thereby ensuring appropriate expression level of EDNRB in human melanocytes. Less