title: Targeted activation of primitive neural stem cells in the mouse brain.
abstract: Primitive neural stem cells (pNSCs) are the earliest NSCs to appear in the developing forebrain. They persist into the adult forebrain where they can generate all cells in the neural lineage and therefore hold great potential for brain regeneration. Thus, pNSCs are an ideal population to target to promote endogenous NSC activation. pNSCs can be isolated from the periventricular region as leukaemia inhibitory factor-responsive cells, and comprise a rare population in the adult mouse brain. We hypothesized that the pup periventricular region gives rise to more clonal pNSC-derived neurospheres but that pup-derived pNSCs are otherwise comparable to adult-derived pNSCs, and can be used to identify selective markers and activators of endogenous pNSCs. We tested the self-renewal ability, differentiation capacity and gene expression profile of pup-derived pNSCs and found them each to be comparable to adult-derived pNSCs, including being GFAP(-) , nestin(mid) , Oct4(+) . Next, we used pup pNSCs to test pharmacological compounds to activate pNSCs to promote endogenous brain repair. We hypothesized that pNSCs could be activated by targeting the cell surface proteins C-Kit and ErbB2, which were enriched in pNSCs relative to definitive NSCs (dNSCs) in an in vitro screen. C-Kit and ErbB2 signalling inhibition had distinct effects on pNSCs and dNSCs in vitro, and when infused directly into the adult brain in vivo. Targeted activation of pNSCs with C-Kit and ErbB2 modulation is a valuable strategy to activate the earliest cell in the neural lineage to contribute to endogenous brain regeneration.
authors.affiliation: Institute of Medical Science, University of Toronto, 160 College St. W. 1130, Toronto, ON, Canada.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Reeve
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Samantha Z
authors.initials: SZ
authors.lastname: Yammine
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Brian
authors.initials: B
authors.lastname: DeVeale
authors.affiliation: Institute of Medical Science, University of Toronto, 160 College St. W. 1130, Toronto, ON, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Derek
authors.initials: D
authors.lastname: van der Kooy
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000166:cytology; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D064231:Nestin / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism / Q000502:physiology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: D005904:Glial Fibrillary Acidic Protein; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D064231:Nestin; D050814:Octamer Transcription Factor-3; D019009:Proto-Oncogene Proteins c-kit; D018719:Erb-b2 Receptor Tyrosine Kinases; D055748:SOXB1 Transcription Factors; D051176:beta Catenin; C507841:Lifr protein, mouse; C577485:Nes protein, mouse; C494174:Pou5f1 protein, mouse; C527783:Sox2 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; C524056:Erbb2 protein, mouse
keywords: cell surface markers; endogenous activation; gene expression; neurogenesis