Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh.
Neural stem cells (NSCs) are controlled by diffusible factors. The transcription factor Sox2 is expressed by NSCs and Sox2 mutations in humans cause defects in the brain and, in particular, in the hippocampus. We deleted Sox2 in the mouse embryonic brain. At birth, the mice showed minor brain defects; shortly afterwards, however, NSCs and neurogenesis were completely lost in the hippocampus, leading to dentate gyrus hypoplasia. Deletion of Sox2 in adult mice also caused hippocampal neurogenesis loss. The hippocampal developmental defect resembles that caused by late sonic hedgehog (Shh) loss. In mutant mice, Shh and Wnt3a were absent from the hippocampal primordium. A SHH pharmacological agonist partially rescued the hippocampal defect. Chromatin immunoprecipitation identified Shh as a Sox2 target. Sox2-deleted NSCs did not express Shh in vitro and were rapidly lost. Their replication was partially rescued by the addition of SHH and was almost fully rescued by conditioned medium from normal cells. Thus, NSCs control their status, at least partly, through Sox2-dependent autocrine mechanisms.
Favaro
Rebecca
R
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milano, Italy.
Valotta
Menella
M
Ferri
Anna L M
AL
Latorre
Elisa
E
Mariani
Jessica
J
Giachino
Claudio
C
Lancini
Cesare
C
Tosetti
Valentina
V
Ottolenghi
Sergio
S
Taylor
Verdon
V
Nicolis
Silvia K
SK
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004254:DNA Nucleotidyltransferases / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000254:growth & development; D020287:In Situ Nick-End Labeling / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007381:Intermediate Filament Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000172:deficiency / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D017077:Culture Media, Conditioned; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D012333:RNA, Messenger; D055748:SOXB1 Transcription Factors; C465570:Shh protein, mouse; C527783:Sox2 protein, mouse; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; D049452:Green Fluorescent Proteins; D004254:DNA Nucleotidyltransferases; C045119:FLP recombinase; D001973:Bromodeoxyuridine