Abstract
During development of the vertebrate inner ear, sensory epithelia and neurons of the statoacoustic ganglion (SAG) arise from lineage-restricted progenitors that proliferate extensively before differentiating into mature post-mitotic cell types. Development of progenitors is regulated by Fgf, Wnt and Notch signaling, but how these pathways are coordinated to achieve an optimal balance of proliferation and differentiation is not well understood. Here we investigate the role in zebrafish of Foxm1, a transcription factor commonly associated with proliferation in developing tissues and tumors. Targeted knockout of foxm1 causes no overt defects in development. Homozygous mutants are viable and exhibit no obvious defects except male sterility. However, the mutant allele acts dominantly to reduce accumulation of SAG neurons, and maternal loss-of-function slightly enhances this deficiency. Neural progenitors are specified normally but, unexpectedly, persist in an early state of rapid proliferation and are delayed in differentiation. Progenitors eventually shift to a slower rate of proliferation similar to wild-type and differentiate to produce a normal number of SAG neurons, although the arrangement of neurons remains variably disordered. Mutant progenitors remain responsive to Fgf and Notch, as blocking these pathways partially alleviates the delay in differentiation. However, the ability of elevated Wnt/beta-catenin to block neural specification is impaired in foxm1 mutants. Modulating Wnt at later stages has no effect on progenitors in mutant or wild-type embryos. Our findings document an unusual role for foxm1 in promoting differentiation of SAG progenitors from an early, rapidly dividing phase to a more mature slower phase prior to differentiation.