Both Notch1 and Notch2 contribute to the regulation of melanocyte homeostasis

Abstract

Notch signaling affects a variety of mammalian stem cells, but there has been limited evidence that a specific Notch molecule regulates adult stem cells. Recently, it was reported that the reduced Notch signaling initiated at the embryonic stage results in a gradual hair graying phenotype after birth. Here we demonstrate that the oral administration of a gamma-secretase inhibitor (GSI) to wild-type adult C57/Bl6 mice led to a gradual increase in gray spots, which remained unchanged for at least 20 weeks after discontinuing the GSI. In GSI-treated mice, there was a severe decrease in unpigmented melanocytes in the bulge/subbulge region where melanocyte stem cells are located. While we confirmed that Notch1+/-Notch2+/- double heterozygous mice with a C57/Bl6 background were born with a normal hair color phenotype and gradually turned gray after the second hair cycle, in the c-kit mutant Wv background, Notch1+/- and Notch2+/- mice had larger white spots on the first appearance of hair than did the Wv/+ mice, which did not change throughout life. Notch1+/-Notch2+/-Wv/+ mice had white hair virtually all over the body at the first appearance of hair and the depigmentation continued to progress thereafter. Using a neural crest organ culture system, GSI blocked the generation of pigmented melanocytes when added to the culture during the period of melanoblast proliferation, but not during the period of differentiation. These observations imply roles of Notch signaling in both development of melanocyte during embryogenesis and maintenance of melanocyte stem cells in adulthood, while the degree of requirement is distinct in these settings: the latter is more sensitive than the former to the reduced Notch signaling. Furthermore, Notch1 and Notch2 cooperates with c-kit signaling during embryogenesis, and they cooperate with each other to regulate melanocyte homeostasis after birth.

Mutations inPOGLUT1in Galli–Galli/Dowling–Degos disease

“…Loss of Notch1 and Notch2 in mice results in abnormal pigmentation; these and other studies suggest that mutations in POGLUT1 resulting in aberrations in Notch signalling would lead to abnormal pigmentation and keratinocyte morphology 9, 10…”

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

“…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. Hence, RBP-Jk-dependent Notch signaling (Schouwey et al, 2010) is required for maintenance of melanoblasts and melanocyte stem cells, and thus to ensure proper hair pigmentation in mouse.…”

Pharmacodynamics of Selective Inhibition of γ-Secretase by Avagacestat

“…Subchronic dosing of GSIs can cause adverse effects in the gastrointestinal (GI) tract, thymus, spleen, skin, and hair in animals, likely resulting from reduced Notch signaling (Milano et al, 2004;Wong et al, 2004;Prasad et al, 2007;Kumano et al, 2008). In the GI tract, GSIs can cause decreased enterocyte differentiation, goblet cell metaplasia, and potential injury to the intestinal epithelium (Milano et al, 2004;Wong et al, 2004).…”