Abstract
The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.
Highlights
The primary cilium is a major cellular sensory organelle that functions as antennae for sensing extracellular information in many cell types [1]
Increased melanin synthesis of the cells exposed to α-MSH was significantly reduced when the cells were treated with Cytochalasin D (Cyto D), a primary cilium formation inducer (Figs 1 and 3)
The suppression of melanogenesis induced by serum starvation was fully rescued and melanogenesis was significantly further elevated in comparison with the control cells by treatment with Ciliobrevin A1 (Cilio A), an inhibitor of primary cilia formation (Figs 2 and 3)
Summary
The primary cilium is a major cellular sensory organelle that functions as antennae for sensing extracellular information in many cell types [1]. Primary cilium formation is regulated by SHH and Wnt signaling [10,11]. Primary cilium formation is activated by the SHH signaling pathway. CAMP production results in the activation of its downstream molecules protein kinase A (PKA) and cAMP-responsive element binding (CREB) protein 1 Activation of these proteins up-regulates the expression of microphthalmia-associated transcription factor (MITF) [18]. We found that the induction of primary cilium formation by Smo-GLI2 signaling suppresses melanin production by reducing the expression of melanogenic enzymes. The suppression of primary cilium formation by ciliobrevin A1 induced melanin synthesis. These effects of primary cilia on pigmentation were confirmed in a human skin model. Our data suggest that ciliogenesis has a critical function in melanogenesis
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