title: Sox2 and Mitf cross-regulatory interactions consolidate progenitor and melanocyte lineages in the cranial neural crest.
abstract: The cellular origin and molecular mechanisms regulating pigmentation of head and neck are largely unknown. Melanocyte specification is controlled by the transcriptional activity of Mitf, but no general logic has emerged to explain how Mitf and progenitor transcriptional activities consolidate melanocyte and progenitor cell fates. We show that cranial melanocytes arise from at least two different cellular sources: initially from nerve-associated Schwann cell precursors (SCPs) and later from a cellular source that is independent of nerves. Unlike the midbrain-hindbrain cluster from which melanoblasts arise independently of nerves, a large center of melanocytes in and around cranial nerves IX-X is derived from SCPs, as shown by genetic cell-lineage tracing and analysis of ErbB3-null mutant mice. Conditional gain- and loss-of-function experiments show genetically that cell fates in the neural crest involve both the SRY transcription factor Sox2 and Mitf, which consolidate an SCP progenitor or melanocyte fate by cross-regulatory interactions. A gradual downregulation of Sox2 in progenitors during development permits the differentiation of both neural crest- and SCP-derived progenitors into melanocytes, and an initial small pool of nerve-associated melanoblasts expands in number and disperses under the control of endothelin receptor B (Ednrb) and Wnt5a signaling.
authors.affiliation: Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 17177 Stockholm, Sweden.
authors.forename: Igor
authors.initials: I
authors.lastname: Adameyko
authors.forename: Francois
authors.initials: F
authors.lastname: Lallemend
authors.forename: Alessandro
authors.initials: A
authors.lastname: Furlan
authors.forename: Nikolay
authors.initials: N
authors.lastname: Zinin
authors.forename: Sergi
authors.initials: S
authors.lastname: Aranda
authors.forename: Satish Srinivas
authors.initials: SS
authors.lastname: Kitambi
authors.forename: Albert
authors.initials: A
authors.lastname: Blanchart
authors.forename: Rebecca
authors.initials: R
authors.lastname: Favaro
authors.forename: Silvia
authors.initials: S
authors.lastname: Nicolis
authors.forename: Moritz
authors.initials: M
authors.lastname: Lübke
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.forename: Carmen
authors.initials: C
authors.lastname: Birchmeier
authors.forename: Ueli
authors.initials: U
authors.lastname: Suter
authors.forename: Ismail
authors.initials: I
authors.lastname: Zaitoun
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Patrik
authors.initials: P
authors.lastname: Ernfors
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D004622:Embryo, Mammalian / Q000196:embryology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D021621:Imaging, Three-Dimensional; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008544:Melanocytes / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism; D010858:Pigmentation / Q000502:physiology*; D010957:Plasmids / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017466:Receptors, Endothelin / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D012583:Schwann Cells / Q000166:cytology; D015398:Signal Transduction / Q000502:physiology; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D034741:RNA, Small Interfering; D017466:Receptors, Endothelin; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse