Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells

Abstract

Melanoblasts (Mbs) are thought to be strictly regulated by cell–cell interactions with epidermal keratinocytes, although the precise molecular mechanism of the regulation has been elusive. Notch signaling, whose activation is mediated by cell–cell interactions, is implicated in a broad range of developmental processes. We demonstrate the vital role of Notch signaling in the maintenance of Mbs, as well as melanocyte stem cells (MSCs). Conditional ablation of Notch signaling in the melanocyte lineage leads to a severe defect in hair pigmentation, followed by intensive hair graying. The defect is caused by a dramatic elimination of Mbs and MSCs. Furthermore, targeted overexpression of Hes1 is sufficient to protect Mbs from the elimination by apoptosis. Thus, these data provide evidence that Notch signaling, acting through Hes1, plays a crucial role in the survival of immature Mbs by preventing initiation of apoptosis.

RBP-Jκ-dependent Notch signaling enhances retinal pigment epithelial cell proliferation in transgenic mice

“…By displacing repressor complexes and recruiting additional coactivators (Jeffries et al, 2002), the binding of NotchIC finally converts RBP-Jk from a transcriptional repressor into an activator and thus initiates transcription of Notch target genes (Radtke et al, 2005;Bray, 2006). In contrast to other organs, the implication of the Notch signaling pathway has only been recently addressed in the pigmentary system (Schouwey and Beermann, 2008), and mouse and human melanocytes have been shown to express members of this signal transduction pathway (Hoek et al, 2004;Haass and Herlyn, 2005;Moriyama et al, 2006;Nishikawa and Osawa, 2007). In vivo analyses have revealed that disruption of the Notch pathway in the melanocyte lineage, by either deleting Notch1 and Notch2 receptors (Schouwey et al, 2007;Kumano et al, 2008), or the transcription factor RBP-Jk (Moriyama et al, 2006;Aubin-Houzelstein et al, 2008), results in a precocious hair graying caused by the progressive loss of the melanocyte population.…”

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

“…Keratinocytes regulate melanocyte growth and expression of melanocyte cell surface receptors via cell adhesion and growth factors, which include E-cadherin, P-cadherin, and desmoglein that are regulated through growth factors such as hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and endothelin-1 (produced by fibroblasts or keratinocytes). Morphogens such as Notch receptors and their ligands also play a role in maintaining melanocyte function and morphology [12]. Loss of keratinocyte regulation characterizes the development of melanoma and is seen in the downregulation of E-and P-cadherins, up-regulation of melanocyte-melanocyte and melanocyte cellfibroblast adhesion molecules such as Mel-CAM and N-cadherin, expression of cell-matrix adhesion molecules such as αvβ3 integrins and increased elaboration of metallo-proteinases [10].…”

“…Ras and its effector pathways Raf-MAPK kinase-ERK and PI3K-Akt are most commonly activated [33,34]. Melanoma also shares many characteristics in common with developmental precursors, stem cells, or melanoblasts, to melanocytes that include activation of developmental signaling pathways [12,35,36]. Specifically, signaling by receptor tyrosine kinases (RTK) (eg, c-Kit), the Wnt signaling pathway, melanocortin signaling pathway (α-MSH/MC1-R/cAMP), as well as loss of the p16 INK4a cyclin-dependent kinase inhibitor are pathways that impact on the expression or function of Mitf, which plays an essential role in melanocyte development and survival [1,37,38].…”

PAUPAR lncRNA suppresses tumourigenesis by H3K4 demethylation in uveal melanoma

“…HES1 is expressed in spinous layers, where it mediates spinous cell gene induction and, thus, the terminal differentiation of epidermal keratinocytes, possibly preventing the premature differentiation of melanocytes [28]. However, in the melanocytic lineage, Notch signalling, acting through HES1, plays a crucial role in the survival of immature melanoblasts and melanocyte stem cells by preventing the initiation of apoptosis [29]. HES1 is preferentially expressed in rectal neuroendocrine tumours, a subset of pancreatic neuroendocrine tumours and is uniformly negative in ileal neuroendocrine tumours [30].…”