title: Fgfr1 is required for cortical regeneration and repair after perinatal hypoxia.
abstract: Chronic postnatal hypoxia causes an apparent loss of cortical neurons that is reversed during recovery (Fagel et al., 2006). The cellular and molecular mechanisms underlying this plasticity are not understood. Here, we show that chronic hypoxia from postnatal days 3 (P3) to 10 causes a 30% decrease in cortical neurons and a 24% decrease in cortical volume. T-brain-1 (Tbr1)(+) and SMI-32(+) excitatory neuron numbers were completely recovered 1 month after the insult, but the mice showed a residual deficit in Parvalbumin(+) and Calretinin(+) GABAergic interneurons. In contrast, hypoxic mice carrying a disrupted fibroblast growth factor receptor-1 (Fgfr1) gene in GFAP+ cells [Fgfr1 conditional knock-out (cKO)], demonstrated a persistent loss of excitatory cortical neurons and a worsening of the interneuron defect. Labeling proliferating progenitors at P17 revealed increased generation of cortical NeuN(+) and Tbr1(+) excitatory neurons in wild-type mice subjected to hypoxic insult, whereas Fgfr1 cKO failed to mount a cortical neurogenetic response. Hypoxic wild-type mice also demonstrated a twofold increase in cell proliferation in the subventricular zone (SVZ) at P17 and a threefold increase in neurogenesis in the olfactory bulb (OB) at P48, compared with normoxic mice. In contrast, Fgfr1 cKO mice had decreased SVZ cell proliferation and curtailed reactive neurogenesis in the OB. Thus, the activation of FGFR-1 in GFAP+ cells is required for neuronal recovery after neonatal hypoxic injury, which is attributable in part to enhanced cortical and OB neurogenesis. In contrast, there is incomplete recovery of inhibitory neurons after injury, which may account for persistent behavioral deficits.
authors.affiliation: Child Study Center, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Devon M
authors.initials: DM
authors.lastname: Fagel
authors.forename: Yosif
authors.initials: Y
authors.lastname: Ganat
authors.forename: Elise
authors.initials: E
authors.lastname: Cheng
authors.forename: John
authors.initials: J
authors.lastname: Silbereis
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohkubo
authors.forename: Laura R
authors.initials: LR
authors.lastname: Ment
authors.forename: Flora M
authors.initials: FM
authors.lastname: Vaccarino
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000473:pathology* / Q000503:physiopathology; D003404:Creatinine / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D000860:Hypoxia / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009416:Nerve Regeneration / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D009830:Olfactory Bulb; D010320:Parvalbumins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D020825:T-Box Domain Proteins
chemical_list: D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D010320:Parvalbumins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D003404:Creatinine; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine