title: Aging Neural Progenitors Lose Competence to Respond to Mitogenic Notch Signaling.
abstract: Drosophila neural stem cells (neuroblasts) are a powerful model system for investigating stem cell self-renewal, specification of temporal identity, and progressive restriction in competence. Notch signaling is a conserved cue that is an important determinant of cell fate in many contexts across animal development; for example, mammalian T cell differentiation in the thymus and neuroblast specification in Drosophila are both regulated by Notch signaling. However, Notch also functions as a mitogen, and constitutive Notch signaling potentiates T cell leukemia as well as Drosophila neuroblast tumors. While the role of Notch signaling has been studied in these and other cell types, it remains unclear how stem cells and progenitors change competence to respond to Notch over time. Notch is required in type II neuroblasts for normal development of their transit amplifying progeny, intermediate neural progenitors (INPs). Here, we find that aging INPs lose competence to respond to constitutively active Notch signaling. Moreover, we show that reducing the levels of the old INP temporal transcription factor Eyeless/Pax6 allows Notch signaling to promote the de-differentiation of INP progeny into ectopic INPs, thereby creating a proliferative mass of ectopic progenitors in the brain. These findings provide a new system for studying progenitor competence and identify a novel role for the conserved transcription factor Eyeless/Pax6 in blocking Notch signaling during development.
authors.affiliation: Howard Hughes Medical Institute, University of Oregon, Eugene, OR 97403, USA; Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Dylan R
authors.initials: DR
authors.lastname: Farnsworth
authors.affiliation: Howard Hughes Medical Institute, University of Oregon, Eugene, OR 97403, USA; Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA.
authors.forename: Omer Ali
authors.initials: OA
authors.lastname: Bayraktar
authors.affiliation: Howard Hughes Medical Institute, University of Oregon, Eugene, OR 97403, USA; Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA; Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA. Electronic address: cdoe@uoregon.edu.
authors.forename: Chris Q
authors.initials: CQ
authors.lastname: Doe
mesh_terms: D000375:Aging; D000818:Animals; D001921:Brain; D054337:Cell Dedifferentiation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D007814:Larva / Q000235:genetics / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; C113278:ey protein, Drosophila