Temporal and spatial gradients of Fgf8 and Fgf17 regulate proliferation and differentiation of midline cerebellar structures

The midbrain-hindbrain (MHB) junction has the properties of an organizer th at patterns the MHB region early in vertebrate development. Fgf8 is thought to mediate this organizer function. In addition to Fgf8, Fgf17 and Fgf18 a re also expressed in the MHB junction. Fgf17 is expressed later and broader than either Fgf8 or Fgf18. Disrupting the Fgf17 gene in the mouse decrease d precursor cell proliferation in the medial cerebellar (vermis) anlage aft er E11.5. Loss of an additional copy of Fgf8 enhanced the phenotype and acc elerated its onset, demonstrating that both molecules cooperate to regulate the size of the precursor pool of cells that develop into the cerebellar v ermis, However, expression patterns of Wnt1, En2, Pax5 and Otx2 were not al tered suggesting that specification and patterning of MHB tissue was not pe rturbed and that these FGFs are not required to pattern the vermis at this stage of development. The consequence of this developmental defect is a pro gressive, dose-dependent loss of the most anterior lobe of the vermis in mi ce lacking Fgf17 and in mice lacking Fgf17 and one copy of Fgf8. Significan tly, the differentiation of anterior vermis neuroepithelium was shifted ros trally and medially demonstrating that FGF also regulates the polarized pro gression of differentiation in the vermis anlage, Finally, this development al defect results in an ataxic gait in some mice.