title: Proneurogenic Ligands Defined by Modeling Developing Cortex Growth Factor Communication Networks.
abstract: The neural stem cell decision to self-renew or differentiate is tightly regulated by its microenvironment. Here, we have asked about this microenvironment, focusing on growth factors in the embryonic cortex at a time when it is largely comprised of neural precursor cells (NPCs) and newborn neurons. We show that cortical NPCs secrete factors that promote their maintenance, while cortical neurons secrete factors that promote differentiation. To define factors important for these activities, we used transcriptome profiling to identify ligands produced by NPCs and neurons, cell-surface mass spectrometry to identify receptors on these cells, and computational modeling to integrate these data. The resultant model predicts a complex growth factor environment with multiple autocrine and paracrine interactions. We tested this communication model, focusing on neurogenesis, and identified IFNγ, Neurturin (Nrtn), and glial-derived neurotrophic factor (GDNF) as ligands with unexpected roles in promoting neurogenic differentiation of NPCs in vivo.
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Yuzwa
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Borrett
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 1A8, Canada.
authors.forename: Geoff
authors.initials: G
authors.lastname: Clarke
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada.
authors.forename: Gonzalo I
authors.initials: GI
authors.lastname: Cancino
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada.
authors.forename: Siraj K
authors.initials: SK
authors.lastname: Zahr
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5G 1A8, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5G 1A8, Canada; McEwen Centre for Regenerative Medicine, University of Toronto, Toronto, ON M5G 1A8, Canada; Departments of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5G 1A8, Canada.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Zandstra
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada. Electronic address: dkaplan@sickkids.ca.
authors.forename: David R
authors.initials: DR
authors.lastname: Kaplan
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1L7, Canada; Institute of Medical Sciences, University of Toronto, Toronto, ON M5G 1A8, Canada; McEwen Centre for Regenerative Medicine, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Department of Physiology, University of Toronto, Toronto, ON M5G 1A8, Canada. Electronic address: fredam@sickkids.ca.
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002540:Cerebral Cortex / Q000254:growth & development* / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000502:physiology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008024:Ligands; D051379:Mice; D008959:Models, Neurological; D009414:Nerve Growth Factors / Q000378:metabolism*; D058953:Neural Stem Cells / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D051101:Neurturin / Q000502:physiology*; D061251:Primary Cell Culture; D059467:Transcriptome / Q000502:physiology
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; C000611649:IFNG protein, mouse; D008024:Ligands; D009414:Nerve Growth Factors; D051101:Neurturin; C495056:Nrtn protein, mouse; D007371:Interferon-gamma