title: Tgfβ signaling regulates temporal neurogenesis and potency of neural stem cells in the CNS.
abstract: How the sequential specification of neurons and progressive loss of potency associated with aging neural progenitors are regulated in vertebrate brain development is poorly understood. By examining a temporal differentiation lineage in the hindbrain, we here identify Tgfβ as a switch signal that executes the transition between early and late phases of neurogenesis and concurrently constrains progenitor potency. Young progenitors have inherent competence to produce late-born neurons, but implementation of late-differentiation programs requires suppression of early identity genes achieved through temporally programmed activation of Tgfβ downstream of Shh signaling. Unexpectedly, we find that sequentially occurring fate-switch decisions are temporally coupled, and onset of Tgfβ signaling appears thereby to impact on the overall lifespan of the temporal lineage. Our study establishes Tgfβ as a regulator of temporal identity and potency of neural stem cells, and provides proof of concept that Tgfβ can be applied to modulate temporal specification of neurons in stem cell engineering.
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: José M
authors.initials: JM
authors.lastname: Dias
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Alekseenko
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Applequist
authors.affiliation: Department of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden. Electronic address: johan.ericson@ki.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Ericson
mesh_terms: D000367:Age Factors; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology*; D002642:Chick Embryo; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000502:physiology*; D054259:Neural Tube; D055495:Neurogenesis / Q000502:physiology*; D009924:Organ Culture Techniques; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D029961:Zebrafish Proteins
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; C109220:NBPhox protein; C436827:Nkx6.2 protein, vertebrate; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D029961:Zebrafish Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I