title: Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis.
abstract: The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.
authors.affiliation: Department of Physiology, Development & Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK.
authors.forename: Sacri R
authors.initials: SR
authors.lastname: Ferrón
authors.forename: Marika
authors.initials: M
authors.lastname: Charalambous
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Radford
authors.forename: Kirsten
authors.initials: K
authors.lastname: McEwen
authors.forename: Hendrik
authors.initials: H
authors.lastname: Wildner
authors.forename: Eleanor
authors.initials: E
authors.lastname: Hind
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Morante-Redolat
authors.forename: Jorge
authors.initials: J
authors.lastname: Laborda
authors.forename: Francois
authors.initials: F
authors.lastname: Guillemot
authors.forename: Steven R
authors.initials: SR
authors.lastname: Bauer
authors.forename: Isabel
authors.initials: I
authors.lastname: Fariñas
authors.forename: Anne C
authors.initials: AC
authors.lastname: Ferguson-Smith
mesh_terms: D000375:Aging / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D001483:Base Sequence; D002135:Calcium-Binding Proteins; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism; D005260:Female; D018392:Genomic Imprinting; D005838:Genotype; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis; D009830:Olfactory Bulb / Q000166:cytology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche / Q000166:cytology* / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020033:Protein Isoforms