Fbxw7 regulation of Notch controls oligodendrocyte number

Abstract

Dissertation under the direction of Professor Bruce H. Appel Oligodendrocytes are specialized glial cells in the vertebrate central nervous system (CNS) that extend processes to wrap axons in myelin sheaths. Their number and distribution must be regulated to ensure uniform axon myelination for rapid conduction of nerve impulses. Elevated levels of Notch signaling activity can block neurogenesis and promote formation of glial cells, but the mechanisms that limit Notch activity to balance formation of neurons and glia from neural precursors are poorly understood. By screening for zebrafish mutations that disrupt oligodendrocyte development we found one allele, called vu56, which produced excess oligodendrocyte progenitor cells (OPCs). Positional cloning revealed that vu56 is a mutation of fbxw7 (f-box protein and wd repeat domain-containing 7), which encodes the substrate recognition component of a ubiquitin ligase that targets Notch 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. Our data indicate that Fbxw7 helps attenuate Notch signaling during zebrafish neural development thereby limiting the number of OPCs.