Abstract
BackgroundIn the developing vertebrate nervous system elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells. The mechanisms that limit Notch activity to balance formation of neurons and glia from neural precursors are poorly understood.ResultsBy screening for mutations that disrupt oligodendrocyte development in zebrafish we found one allele, called vu56, that produced excess oligodendrocyte progenitor cells (OPCs). Positional cloning revealed that the vu56 allele is a mutation of fbxw7, which encodes the substrate recognition component of a ubiquitin ligase that targets Notch and other proteins for degradation. To investigate the basis of the mutant phenotype we performed in vivo, time-lapse imaging, which revealed that the increase in OPC number resulted from production of extra OPCs by ventral spinal cord precursors and not from changes in OPC proliferation or death. Notch signaling activity was elevated in spinal cord precursors of fbxw7 mutant zebrafish and inhibition of Notch signaling suppressed formation of excess OPCs.ConclusionNotch signaling promotes glia cell formation from neural precursors in vertebrate embryos. Our data indicate that Fbxw7 helps attenuate Notch signaling during zebrafish neural development thereby limiting the number of OPCs.
Highlights
In the developing vertebrate nervous system elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells
Mutation of fbxw7 produces excess oligodendrocyte lineage cells By screening for changes in the number and distribution of oligodendrocyte lineage cells marked by Tg(olig2: EGFP) reporter gene expression, we identified a mutation designated vu56, which, when homozygous, resulted in excess EGFP+ dorsal spinal cord cells at 3 days post fertilization (Figure 1A, B)
Our work indicates that negative regulation of Notch activity by Fbxw7 ubiquitin ligase limits the number of neural precursors specified for oligodendrocyte fate
Summary
In the developing vertebrate nervous system elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells. Spinal cord precursors initiate expression of transcription factors Sox, NFIA and NFIB prior to gliogenesis and these factors promote timely formation of oligodendrocytes and astrocytes [9,10], raising the possibility that they contribute to a mechanism that causes neural precursors to switch from neuron to glial cell production. Loss of Notch signaling in vertebrate embryos results in loss of neural precursors, formation of excess early-born neurons and a deficit of glial cells, including oligodendrocytes [11,12,13,14,15,16,17] This occurs, in part, by elevated expression of the proneural genes Ngn and Ngn2 [18], which promote cell cycle exit and neurogenesis with the consequent loss of later-born glia. How Notch activity is controlled to balance neuron and OPC specification remains poorly understood
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