RESUMO
Oligodendrocyte precursor development in the embryonic spinal cord is thought to be regulated by the secreted signal, Sonic hedgehog (Shh). Such precursors can be identified by the expression of Olig genes, encoding basic helix-loop-helix factors, in the spinal cord and brain. However, the signaling pathways that govern oligodendrocyte precursor (OLP) development in the rostral central nervous system are poorly understood. Here, we show that Shh is required for oligodendrocyte development in the mouse forebrain and spinal cord, and that Shh proteins are both necessary and sufficient for OLP production in cortical neuroepithelial cultures. Moreover, adenovirus-mediated Olig1 ectopic expression can promote OLP formation independent of Shh activity. Our results demonstrate essential functions for Shh during early phases of oligodendrocyte development in the mammalian central nervous system. They further suggest that a key role of Shh signaling is activation of Olig genes.
Assuntos
Encéfalo/embriologia , Proteínas de Ligação a DNA , Oligodendroglia/fisiologia , Transativadores/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Células Cultivadas , Senescência Celular/fisiologia , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário e Fetal , Proteínas Hedgehog , Proteínas do Tecido Nervoso/farmacologia , Oligodendroglia/efeitos dos fármacos , Prosencéfalo/embriologia , Ratos , Ratos Sprague-Dawley , Medula Espinal/embriologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologiaRESUMO
Sciatic nerve axons in cyclin D1 knockout mice develop normally, become properly ensheathed by Schwann cells, and appear to function normally. However, in the Wallerian degeneration model of nerve injury, the mitotic response of Schwann cells is completely inhibited. The mitotic block is Schwann cell autonomous and developmentally regulated. Rescue analysis (by "knockin" of cyclin E) indicates that D1 protein, rather than regulatory elements of the D1 gene, provides the essential Schwann cell function. Genetic inhibition of the Schwann cell cycle shows that neuronal responses to nerve injury are surprisingly independent of Schwann cell mitotic responses. Even axonal regrowth into the distal zone of a nerve crush injury is not markedly impaired in cyclin D1-/- mice.
Assuntos
Ciclina D1/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Genes de Troca/fisiologia , Regeneração Nervosa/fisiologia , Células de Schwann/fisiologia , Animais , Divisão Celular/fisiologia , Células Cultivadas , Senescência Celular/fisiologia , Ciclina D1/deficiência , Ciclina D1/genética , Ciclina E/genética , Ciclina E/fisiologia , Gânglios Espinais/citologia , Gânglios Espinais/embriologia , Camundongos , Camundongos Knockout/genética , Mitose , Fenótipo , Ratos , Valores de Referência , Células de Schwann/patologia , Degeneração Walleriana/patologiaRESUMO
During development, basic helix-loop-helix (bHLH) proteins regulate formation of neurons from multipotent progenitor cells. However, bHLH factors linked to gliogenesis have not been described. We have isolated a pair of oligodendrocyte lineage genes (Olg-1 and Olg-2) that encode bHLH proteins and are tightly associated with development of oligodendrocytes in the vertebrate central nervous system (CNS). Ectopic expression of Olg-1 in rat cortical progenitor cell cultures promotes formation of oligodendrocyte precursors. In developing mouse embryos, Olg gene expression overlaps but precedes the earliest known markers of the oligodendrocyte lineage. Olg genes are expressed at the telencephalon-diencephalon border and adjacent to the floor plate, a source of the secreted signaling molecule Sonic hedgehog (Shh). Gain- and loss-of-function analyses in transgenic mice demonstrate that Shh is both necessary and sufficient for Olg gene expression in vivo.