Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone.
We sought to address the fundamental question of how stem cell microenvironments can regulate self-renewal. We found that Notch was active in astroglia-like neural stem cells (NSCs), but not in transit-amplifying progenitors of the murine subependymal zone, and that the level of Notch transcriptional activity correlated with self-renewal and multipotency. Moreover, dividing NSCs appeared to balance renewal with commitment via controlled segregation of Notch activity, leading to biased expression of known (Hes1) and previously unknown (Egfr) Notch target genes in daughter cells. Pigment epithelium-derived factor (PEDF) enhanced Notch-dependent transcription in cells with low Notch signaling, thereby subverting the output of an asymmetrical division to the production of two highly self-renewing cells. Mechanistically, PEDF induced a non-canonical activation of the NF-kappaB pathway, leading to the dismissal of the transcriptional co-repressor N-CoR from specific Notch-responsive promoters. Our data provide a basis for stemness regulation in vascular niches and indicate that Notch and PEDF cooperate to regulate self-renewal.
Andreu-Agulló
Celia
C
Departamento de Biología Celular and CIBER en Enfermedades Neurodegenerativas, Universidad de Valencia, Burjassot, Spain.
Morante-Redolat
José Manuel
JM
Delgado
Ana C
AC
Fariñas
Isabel
I
D053687:Adult Stem Cells / Q000166:cytology* / Q000378:metabolism*; D000367:Age Factors; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004805:Ependyma / Q000166:cytology*; D066246:ErbB Receptors / Q000235:genetics; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000072056:Transcription Factor HES-1; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D000099174:Pigment Epithelium-Derived Factor
D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D005136:Eye Proteins; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D056971:Nuclear Receptor Co-Repressor 1; D051881:Receptor, Notch1; D015843:Serpins; D000072056:Transcription Factor HES-1; D051996:Transcription Factor RelA; D000099174:Pigment Epithelium-Derived Factor; C489734:Hes1 protein, mouse; C539128:Ncor1 protein, mouse; C497762:Notch1 protein, mouse