RRC ID 3887
Author Blanpain C, Lowry WE, Pasolli HA, Fuchs E.
Title Canonical notch signaling functions as a commitment switch in the epidermal lineage.
Journal Genes Dev
Abstract Mammalian epidermis consists of a basal layer of proliferative progenitors that gives rise to multiple differentiating layers to provide a waterproof envelope covering the skin surface. To accomplish this, progenitor cells must detach from the basal layer, move upward, and execute a terminal differentiation program consisting of three distinct stages: spinous, granular layer, and stratum corneum. Notch signaling has been implicated in late stages of differentiation, but the commitment switch remains unknown. Here we show with loss and gain-of-function studies that active Notch intracellular domain (NICD) and its obligate canonical signaling partner RBP-J act at the basal/suprabasal juncture to induce spinous and down-regulate basal fate. Spinous layers are absent in RBP-J conditional null epidermis and expanded when Notch1 signaling is elevated transgenically in epidermis. We show that RBP-J is essential for mediating both spinous gene activation and basal gene repression. In contrast, the NICD/RBP-J target gene Hes1 is expressed in spinous layers and mediates spinous gene induction but not basal gene repression. These data uncover an early role for RBP-J and Notch in commitment of epidermal cells to terminally differentiate and reveal that spinous gene induction is mediated by a Hes1-dependent mechanism, while basal gene repression occurs independently of Hes1.
Volume 20(21)
Pages 3022-35
Published 2006-11-1
DOI 10.1101/gad.1477606
PII 20/21/3022
PMID 17079689
PMC PMC1620020
MeSH Animals Basic Helix-Loop-Helix Transcription Factors / genetics Basic Helix-Loop-Helix Transcription Factors / metabolism Cell Differentiation Cell Lineage / genetics* Cell Proliferation DNA-Binding Proteins / metabolism Epidermal Cells Epidermis / growth & development* Epidermis / metabolism Gene Expression Gene Expression Regulation, Developmental* Homeodomain Proteins / genetics Homeodomain Proteins / metabolism Mice Mice, Mutant Strains Protein Structure, Tertiary Receptor, Notch1 / genetics Receptor, Notch1 / metabolism* Signal Transduction Skin / cytology Skin / growth & development Skin / metabolism Transcription Factor HES-1 Transcriptional Activation
IF 9.527
Times Cited 268
DNA material RBP-J (RDB01801) pCMX-N/RBP-J (R218H) (RDB03022) pCMX-N/VP16-RBP-J (RDB03023).