Melanocytes evolved to produce the melanin that gives colour to our hair, eyes and skin. The melanocyte lineage also gives rise to melanoma, the most lethal form of skin cancer. The melanocyte lineage differentiates from neural crest cells during development, and most melanocytes reside in the skin and hair, where they are replenished by melanocyte stem cells. Because the molecular mechanisms necessary for melanocyte specification, migration, proliferation and differentiation are co-opted during melanoma initiation and progression, studying melanocyte development is directly relevant to human disease. Here, through the lens of advances in cellular omic and genomic technologies, we review the latest findings in melanocyte development and differentiation, and how these developmental pathways become dysregulated in disease.

Hyperpigmented dermatoses are characterized by increased skin pigmentation caused by genetic, environmental factors and inflammation, which lasts a long time and is difficult to treat. Ultraviolet (UV), especially ultraviolet B (UVB), is the primary external factor inducing skin pigmentation. However, the specific regulatory mechanisms are not fully understood. Through analysis of GEO datasets from four UV-exposed skin cell/tissue samples, we found that TRPS1 is the only gene differentially expressed in multiple datasets (GSE22083, GSE67098 and GSE70280) and highly positively correlated with the expression of key melanogenesis genes. Consistently, we observed that TRPS1 is highly expressed in sun-exposed skin tissues compared to non-exposed skin. Additionally, the expression of TRPS1 was also significantly upregulated after UVB irradiation in isolated skin tissues and melanocytes, while knockdown of TRPS1 expression inhibited the UVB-induced melanogenesis. Further research revealed that overexpression of TRPS1 increased melanin content and tyrosinase activity in MNT1 cells, as well as upregulated the expression levels of key melanogenesis genes (MITF, TYR, TYRP1, DCT). In contrast, inhibition of TRPS1 expression showed the opposite effect. Moreover, we found that TRPS1 can bind to the promoter region of MITF, inhibiting the expression of MITF can antagonize the melanogenesis induced by TRPS1. In conclusion, UVB-induced TRPS1 promotes melanogenesis by activating the transcriptional activity of MITF.

Coxiella burnetii is a highly infectious, Gram-negative, obligate intracellular bacterium and the causative agent of human Q fever. The Coxiella Containing Vacuole (CCV) is a modified phagolysosome that forms through fusion with host endosomes and lysosomes. While an initial acidic pH < 4.7 is essential to activate Coxiella metabolism, the mature, growth-permissive CCV has a luminal pH of ~5.2 that remains stable throughout infection. Inducing CCV acidification to a lysosomal pH (~4.7) causes Coxiella degradation, suggesting that Coxiella regulates CCV pH. Supporting this hypothesis, Coxiella blocks host lysosomal biogenesis, leading to fewer host lysosomes available to fuse with the CCV. Host cell lysosome biogenesis is primarily controlled by the transcription factor EB (TFEB), which binds Coordinated Lysosomal Expression And Regulation (CLEAR) motifs upstream of genes involved in lysosomal biogenesis and function. TFEB is a member of the microphthalmia/transcription factor E (MiT/TFE) protein family, which also includes MITF, TFE3, and TFEC. This study examines the roles of MiT/TFE proteins during Coxiella infection. We found that in cells lacking TFEB, both Coxiella growth and CCV size increase. Conversely, TFEB overexpression or expression in the absence of other family members leads to significantly less bacterial growth and smaller CCVs. TFE3 and MITF do not appear to play a significant role during Coxiella infection. Surprisingly, we found that Coxiella actively blocks TFEB nuclear translocation in a Type IV Secretion System-dependent manner, thus decreasing lysosomal biogenesis. Together, these results suggest that Coxiella inhibits TFEB nuclear translocation to limit lysosomal biogenesis, thus avoiding further CCV acidification through CCV-lysosomal fusion.
OBJECTIVE: The obligate intracellular bacterial pathogen Coxiella burnetii causes the zoonotic disease Q fever, which is characterized by a debilitating flu-like illness in acute cases and life-threatening endocarditis in patients with chronic disease. While Coxiella survives in a unique lysosome-like vacuole called the Coxiella Containing Vacuole (CCV), the bacterium inhibits lysosome biogenesis as a mechanism to avoid increased CCV acidification. Our results establish that transcription factor EB (TFEB), a member of the microphthalmia/transcription factor E (MiT/TFE) family of transcription factors that regulate lysosomal gene expression, restricts Coxiella infection. Surprisingly, Coxiella blocks TFEB translocation from the cytoplasm to the nucleus, thus downregulating the expression of lysosomal genes. These findings reveal a novel bacterial mechanism to regulate lysosomal biogenesis.

The excessive production of melanin can cause skin diseases and hyperpigmentation. In this study, resveratrol contained in Dongjin rice seed (DJ526) was increased through callus induction. The antioxidant capacity of resveratrol-enriched rice callus was evaluated using the ABTS radical scavenging method and was equivalent to that of vitamin C. DJ526 rice callus extract significantly increased antioxidant activities in a concentration-dependent manner. The anti-melanogenesis effects of DJ526 rice callus extract were also evaluated in melan-a cells. Resveratrol-enriched rice callus extract significantly (i) decreased the size and number of melanin-containing cells, (ii) suppressed the activity of cellular tyrosinase and melanin content, (iii) downregulated the expression of microphthalmia-associated transcription factor, tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2, (iv) increased the expression of phosphorylated extracellular signal-regulated kinase 1/2 and protein kinase B, and (v) inhibited the activation of phosphorylated p38 in melan-a cells. From the above observations, DJ526 rice callus extract showed strong antioxidant and anti-melanogenesis activity at the concentration test. These findings indicate the potential of resveratrol-enriched rice callus as a novel agent for controlling hyperpigmentation.

OBJECTIVE: Methylsulfonylmethane (MSM), which contains organic sulphur, has been used for a long time as a medicinal ingredient because of its benefits to human health. MSM is reported to be protective against certain skin disorders, but it is unknown whether it affects melanin synthesis. Therefore, in our current research, we examined the possibility of MSM controlling the production of melanin in Mel-Ab melanocytes.
METHODS: In Mel-Ab cells, melanin contents and tyrosinase activities were assessed and quantified. The expression of microphthalmia-associated transcription factor (MITF) and tyrosinase was evaluated using western blot analysis, while MSM-induced signalling pathways were investigated.
RESULTS: The MSM treatment significantly resulted in a dose-dependent increase in melanin production. Furthermore, MSM elevated melanin-related proteins, including MITF and tyrosinase. However, the rate-limiting enzyme of melanin production, tyrosinase, was not directly influenced by it. Therefore, we investigated potential melanogenesis-related signalling pathways that may have been triggered by MSM. Our findings showed that MSM did not influence the signalling pathways associated with glycogen synthase kinase 3β, cAMP response-element binding protein, extracellular signal-regulated kinase, or p38 mitogen-activated protein kinase. However, MSM phosphorylated c-Jun N-terminal kinases/stress-activated protein kinase (JNK/SAPK), which is known to induce melanogenesis. SP600125, a specific JNK inhibitor, inhibited MSM-induced melanogenesis.
CONCLUSIONS: Taken together, our study indicates that MSM induces melanin synthesis and may serve as a therapeutic option for hypopigmentary skin disorders such as vitiligo.
ZIEL: Methylsulfonylmethan (MSM), das organischen Schwefel enthält, wird aufgrund seiner Vorteile für die menschliche Gesundheit seit langem als medizinischer Inhaltsstoff verwendet. Es wird berichtet, dass MSM vor bestimmten Hauterkrankungen schützt, es ist jedoch nicht bekannt, ob es die Melaninsynthese beeinflusst. Daher haben wir in unserer aktuellen Forschung die Möglichkeit untersucht, dass MSM die Melaninproduktion in Mel‐Ab‐Melanozyten kontrolliert.
METHODS: In Mel‐Ab‐Zellen wurden der Melaningehalt und die Tyrosinase‐Aktivitäten bewertet und quantifiziert. Die Expression von Mikrophthalmie‐assoziiertem Transkriptionsfaktor (MITF) und Tyrosinase wurde mittels Western‐Blot‐Analyse bewertet, während MSM‐induzierte Signalwege untersucht wurden.
UNASSIGNED: Die MSM‐Behandlung führte signifikant zu einer dosisabhängigen Steigerung der Melaninproduktion. Darüber hinaus erhöhte MSM Melanin‐verwandte Proteine, einschließlich MITF und Tyrosinase. Das geschwindigkeitsbestimmende Enzym der Melaninproduktion, die Tyrosinase, wurde davon jedoch nicht direkt beeinflusst. Daher untersuchten wir mögliche Signalwege im Zusammenhang mit der Melanogenese, die möglicherweise durch MSM ausgelöst wurden. Unsere Ergebnisse zeigten, dass MSM keinen Einfluss auf die Signalwege hatte, die mit der Glykogensynthase‐Kinase 3β, dem cAMP‐Response‐Element‐Bindungsprotein, der extrazellulären signalregulierten Kinase oder der p38‐Mitogen‐aktivierten Proteinkinase verbunden sind. Allerdings phosphorylierte MSM c‐Jun N‐terminale Kinasen/stressaktivierte Proteinkinase (JNK/SAPK), von der bekannt ist, dass sie die Melanogenese induziert. SP600125, ein spezifischer JNK‐Inhibitor, hemmte die MSM‐induzierte Melanogenese.
UNASSIGNED: Zusammenfassend lässt unsere Studie darauf schließen, dass MSM die Melaninsynthese induziert und als Therapieoption für hypopigmentäre Hauterkrankungen wie Vitiligo dienen kann.
OBJECTIVE: le méthylsulfonylméthane (MSM), qui contient du soufre organique, est utilisé depuis longtemps comme ingrédient médicamenteux en raison de ses bénéfices pour la santé humaine. Le MSM aurait un effet protecteur contre certains troubles cutanés, mais on ignore s’il affecte la synthèse de la mélanine. Par conséquent, dans notre étude actuelle, nous avons examiné la possibilité que le MSM contrôle la production de mélanine dans les mélanocytes Mel‐Ab. MÉTHODES: dans les cellules Mel‐Ab, la teneur en mélanine et les activités de la tyrosinase ont été évaluées et quantifiées. L’expression du facteur de transcription associé à la microphtalmie (microphthalmia‐associated transcription factor, MITF) et de la tyrosinase a été évaluée à l’aide d’une analyse Western blot, tandis que les voies de signalisation induites par le MSM ont été étudiées. RÉSULTATS: le traitement par MSM a entraîné de manière significative une augmentation dose‐dépendante de la production de mélanine. En outre, le MSM a élevé les taux de protéines liées à la mélanine, notamment le MITF et la tyrosinase. Cependant, l’enzyme limitant la vitesse de production de la mélanine, la tyrosinase, n’a pas été directement influencée par celui‐ci. Par conséquent, nous avons étudié les voies de signalisation potentielles liées à la mélanogenèse qui pourraient avoir été déclenchées par le MSM. Nos résultats ont montré que le MSM n’influe pas sur les voies de signalisation associées à la protéine glycogène synthase kinase 3β, à la protéine de liaison à l’élément de réponse AMPc, à la kinase régulée par signal extracellulaire ou à la protéine kinase activée par mitogène p38. Cependant, le MSM a phosphorylé les kinases N‐terminales c‐Jun/la protéine kinase activée par le stress (c‐Jun N‐terminal kinases/stress‐activated protein kinase, JNK/SAPK), réaction connue pour induire une mélanogenèse. Le SP600125, un inhibiteur spécifique de la JNK, a inhibé la mélanogenèse induite par le MSM.
CONCLUSIONS: dans l’ensemble, notre étude indique que le MSM induit la synthèse de la mélanine et peut servir d’option thérapeutique pour les troubles cutanés hypopigmentaires tels que le vitiligo.

Melanocytes, located in the epidermis\' basal layer, are responsible for melanin pigment production, crucial for skin coloration and protection against UV radiation-induced damage. Melanin synthesis is intricately regulated by various factors, including the Wnt signaling pathway, particularly mediated by the microphthalmia-associated transcription factor (MITF). While MITF is recognized as a key regulator of pigmentation, its regulation by the Wnt pathway remains poorly understood. This study investigates the role of Sfrp5pepD, a peptide antagonist of the Wnt signaling pathway, in modulating melanogenesis and its potential therapeutic implications for pigmentary disorders. To tackle this issue, we investigated smaller peptides frequently utilized in cosmetics or pharmaceuticals. Nevertheless, there is a significant scarcity of reports on peptides associated with melanin-related signal modulation or inhibiting melanin production. Results indicate that Sfrp5pepD effectively inhibits Wnt signaling by disrupting the interaction between Axin-1 and β-catenin, thus impeding downstream melanogenic processes. Additionally, Sfrp5pepD suppresses the interaction between MITF and β-catenin, inhibiting their nuclear translocation and downregulating melanogenic enzyme expression, ultimately reducing melanin production. These inhibitory effects are validated in cell culture models suggesting potential clinical applications for hyperpigmentation disorders. Overall, this study elucidates the intricate interplay between Wnt signaling and melanogenesis, highlighting Sfrp5pepD as a promising therapeutic agent for pigmentary disorders. Sfrp5pepD, with a molecular weight of less than 500 Da, is anticipated to penetrate the skin unlike SFRPs. This suggests a strong potential for their use as cosmetics or transdermal absorption agents. Additional investigation into its mechanisms and clinical significance is necessary to enhance its effectiveness in addressing melanin-related skin conditions.

The skin-brain axis has been suggested to play a role in several pathophysiological conditions, including opioid addiction, Parkinson\'s disease and many others. Recent evidence suggests that pathways regulating skin pigmentation may directly and indirectly regulate behaviour. Conversely, CNS-driven neural and hormonal responses have been demonstrated to regulate pigmentation, e.g., under stress. Additionally, due to the shared neuroectodermal origins of the melanocytes and neurons in the CNS, certain CNS diseases may be linked to pigmentation-related changes due to common regulators, e.g., MC1R variations. Furthermore, the HPA analogue of the skin connects skin pigmentation to the endocrine system, thereby allowing the skin to index possible hormonal abnormalities visibly. In this review, insight is provided into skin pigment production and neuromelanin synthesis in the brain and recent findings are summarised on how signalling pathways in the skin, with a particular focus on pigmentation, are interconnected with the central nervous system. Thus, this review may supply a better understanding of the mechanism of several skin-brain associations in health and disease.

Structural variations (SVs) are a major source of domestication and improvement traits. We present the first duck pan-genome constructed using five genome assemblies capturing ∼40.98 Mb new sequences. This pan-genome together with high-depth sequencing data (∼46.5×) identified 101,041 SVs, of which substantial proportions were derived from transposable element (TE) activity. Many TE-derived SVs anchoring in a gene body or regulatory region are linked to duck\'s domestication and improvement. By combining quantitative genetics with molecular experiments, we, for the first time, unraveled a 6945 bp Gypsy insertion as a functional mutation of the major gene IGF2BP1 associated with duck bodyweight. This Gypsy insertion, to our knowledge, explains the largest effect on bodyweight among avian species (27.61% of phenotypic variation). In addition, we also examined another 6634 bp Gypsy insertion in MITF intron, which triggers a novel transcript of MITF, thereby contributing to the development of white plumage. Our findings highlight the importance of using a pan-genome as a reference in genomics studies and illuminate the impact of transposons in trait formation and livestock breeding.

Skin hyperpigmentation is mainly caused by excessive synthesis of melanin; however, there is still no safe and effective therapy for its removal. Here, we found that the dermal freezer was able to improve UVB-induced hyperpigmentation of guinea pigs without causing obvious epidermal damage. We also mimic freezing stimulation at the cellular level by rapid freezing and observed that freezing treatments <2.5 min could not decrease cell viability or induce cell apoptosis in B16F10 and Melan-A cells. Critically, melanin content and tyrosinase activity in two cells were greatly reduced after freezing treatments. The dramatic decrease in tyrosinase activity was associated with the downregulation of MITF, TYR, TRP-1 and TRP-2 protein expression in response to freezing treatments for two cells. Furthermore, our results first demonstrated that freezing treatments significantly reduced the levels of p-GSK3β and β-catenin and the nuclear accumulation of β-catenin in B16F10 and Melan-A cells. Together, these data suggest that fast freezing treatments can inhibit melanogenesis-related gene expression in melanocytes by regulating the Wnt/β-catenin signalling pathway. The inhibition of melanin production eventually contributed to the improvement in skin hyperpigmentation induced by UVB. Therefore, fast freezing treatments may be a new alternative of skin whitening in the clinic in the future.

Calcium (Ca2+) plays a pivotal role in cellular signal transmission by triggering downstream signaling in response to an increase in the cytosolic Ca2+ concentration. Intracellular organelles serve as Ca2+ stores that induce differently shaped Ca2+ signals. We discuss a study by Yuan et al. that investigated the interplay between the lysosomal two-pore channel 2 (TPC2) and endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptors (IP3Rs).