Notch signaling via Hes1 transcription factor maintains survival of melanoblasts and melanocyte stem cells.
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.
Moriyama
Mariko
M
Laboratory for Stem Cell Biology, RIKEN Center for Developmental Biology, Hyogo 650-0047, Japan.
Osawa
Masatake
M
Mak
Siu-Shan
SS
Ohtsuka
Toshiyuki
T
Yamamoto
Norio
N
Han
Hua
H
Delmas
Véronique
V
Kageyama
Ryoichiro
R
Beermann
Friedrich
F
Larue
Lionel
L
Nishikawa
Shin-Ichi
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004151:Dipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000378:metabolism; D015870:Gene Expression / Q000235:genetics; D006200:Hair Color / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D000072101:Jagged-2 Protein; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D000072056:Transcription Factor HES-1
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D019746:Intramolecular Oxidoreductases; D000072101:Jagged-2 Protein; D008565:Membrane Proteins; D051881:Receptor, Notch1; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C490503:Jag2 protein, mouse; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497762:Notch1 protein, mouse; C042501:dopachrome isomerase