Hoeck et al. found that, in the absence of Fbw7, the SCF substrates Notch and c-Jun are insufficiently degraded. Their ensuing accumulation inhibits differentiation and increases apoptotic death of neural progenitors. In the developing mouse brain, lack of Fbw7 increased the number of cells expressing immature progenitor markers and reduced neuron numbers by about half, but had no effect on glial numbers. Loss of one c-Jun allele reduced apoptosis in the Fbw7-depleted developing brain and partially restored cortical neuron numbers, but it did not normalize the number of immature progenitors. Conversely, inhibiting Notch signaling reduced immature progenitor numbers and also partially restored cortical neurons.
Fbw7 initiates the proteasomal degradation of several well-known mitotic molecules in addition to Notch and c-Jun, however none of these other known substrates were dysregulated in the Fbw7-depleted brain. Fbw7 is an important tumor suppressor gene mutated in diverse cancers. Hoeck et al., however, are the first to show that Fbw7 is also important for the development of the nervous system.
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