Abstract
The mammalian integumentary system plays important roles in body homeostasis, and dysfunction of melanogenesis or epidermal development may lead to a variety of skin diseases, including melanoma. Skin pigmentation in humans and coat color in fleece-producing animals are regulated by many genes. Among them, microphthalmia-associated transcription factor (MITF) and paired-box 3 (PAX3) are at the top of the cascade and regulate activities of many important melanogenic enzymes. Here, we report for the first time that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of MITF and PAX3. Cdk5 knockdown in mice causes a lightened coat color, a polarized distribution of melanin and hyperproliferation of basal keratinocytes. Reduced expression of Keratin 10 (K10) resulting from Cdk5 knockdown may be responsible for an abnormal epidermal structure. In contrast, overexpression of Cdk5 in sheep (Ovis aries) only produces brown patches on a white background, with no other observable abnormalities. Collectively, our findings show that Cdk5 has an important functional role in the regulation of melanin production and transportation and in normal development of the integumentary system.
Highlights
Pigmentation of the skin, hair, and eyes depends primarily on the synthesis and distribution of melanin that is produced by melanocytes[2]
microphthalmia-associated transcription factor (MITF) and paired-box 3 (PAX3) regulate the transcription of genes for three major pigmentation enzymes, namely, tyrosinase (TYR), tyrosine related protein-1 (TYRP1), and tyrosine related protein-2 (TYRP2; dopachrome tautomerase (DCT))[16,17,18,19]
PAX3 directly interacts with the SRY-related HMG-box (Sox10) and can activate MITF expression in a synergistic manner[21] while simultaneously competing with MITF for occupancy of an enhancer required for the expression of TYRP222
Summary
Pigmentation of the skin, hair, and eyes depends primarily on the synthesis and distribution of melanin that is produced by melanocytes[2]. More than 125 genes have been identified as being involved in the regulation of melanocyte development and melanogenesis at different pathways, which act at transcriptional, translational, and www.nature.com/scientificreports/. Melanocortin receptor type 1 (MC1R) is one of seven transmembrane G protein-coupled receptors involved in regulation of melanogenic activity In melanocytes, it can regulate melanogenesis, cell proliferation and survival[7,8]. It can regulate melanogenesis, cell proliferation and survival[7,8] It is activated upon binding of MSH or ACTH peptides (products of POMC processing) as a result of intracellular cAMP accumulation[10]. An analysis of the transcriptome profile of alpaca skin with different hair colors has revealed that cyclin-dependent kinase 5 (Cdk5) is a candidate gene for alpaca fleece quality, coat color and fiber growth and development[25]. A functional role for Cdk[5] in melanogenesis and epidermal development is still lacking
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