title: Caspase-9 regulates apoptosis/proliferation balance during metamorphic brain remodeling in Xenopus.
abstract: During anuran metamorphosis, the tadpole brain is transformed producing the sensorial and motor systems required for the frog's predatory lifestyle. Nervous system remodeling simultaneously implicates apoptosis, cell division, and differentiation. The molecular mechanisms underlying this remodeling have yet to be characterized. Starting from the observation that active caspase-9 and the Bcl-X(L) homologue, XR11 are highly expressed in tadpole brain during metamorphosis, we determined their implication in regulating the balance of apoptosis and proliferation in the developing tadpole brain. In situ hybridization showed caspase-9 mRNA to be expressed mainly in the ventricular area, a site of neuroblast proliferation. To test the functional role of caspase-9 in equilibrating neuroblast production and elimination, we overexpressed a dominant-negative caspase-9 protein, DN9, in the tadpole brain using somatic gene transfer and germinal transgenesis. In both cases, abrogating caspase-9 activity significantly decreased brain apoptosis and increased numbers of actively proliferating cells in the ventricular zone. Moreover, overexpression of XR11 with or without DN9 was also effective in decreasing apoptosis and increasing cell division in the tadpole brain. We conclude that XR11 and caspase-9, two key members of the mitochondrial death pathway, are implicated in controlling the proliferative status of neuroblasts in the metamorphosing Xenopus brain. Modification of their expression during the critical period of metamorphosis alters the outcome of metamorphic neurogenesis, resulting in a modified brain phenotype in juvenile Xenopus.
authors.affiliation: Evolution des Régulations Endocriniennes, Muséum National d'Histoire Naturelle, Unité Mixte de Recherche-Centre National de la Recherche Scientifique 5166, Unité Scientifique du Muséum 501, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Coen
authors.forename: Karine
authors.initials: K
authors.lastname: Le Blay
authors.forename: Isaline
authors.initials: I
authors.lastname: Rowe
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Demeneix
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002470:Cell Survival; D002552:Cerebral Ventricles / Q000166:cytology / Q000201:enzymology; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D005799:Genes, Dominant; D007814:Larva / Q000201:enzymology / Q000502:physiology; D008675:Metamorphosis, Biological / Q000502:physiology*; D008938:Mitosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000378:metabolism; D014982:Xenopus laevis / Q000502:physiology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C494809:BCL2L1 protein, Xenopus; D012333:RNA, Messenger; D029867:Xenopus Proteins; D051020:bcl-X Protein; D053453:Caspase 9