Neurons of the cerebellum coordinate fine motor activities and many disease processes can affect cerebellar development and function. Furthermore, cerebellar granule cells are thought to give rise to medulloblastoma, the most common malignant pediatric brain tumor. Despite the highly stereotyped cerebellar architecture, little is known about the molecular mechanisms that regulate the development and pathophysiology of the cerebellum. Fibroblast growth factors (FGFs) are expressed throughout murine CNS development and some FGFs are expressed in adult neuronal tissue. However, very little is known about the function of these molecules in terms of CNS development and pathophysiology. We have therefore chosen to study three members of the FGF family with unique expression patterns that make them likely candidates for regulators of midbrain-hindbrain development. We have recently identified two novel murine Fgfs, called Fgf17 and Fgf18. These two Fgfs are closely related to Fgf8 and Fgf8 are expressed at the midbrain-hindbrain function, although later in development. These observations suggest that these Fgfs may all be involved in midbrain- hindbrain development. We have recently generated a line of mice in which one of these Fgfs, Fgf17, has been disrupted. Fgf17 -/- are viable but demonstrate loss of anterior cerebellar structures. Fgf14 is a member of a sub-family of Fgfs that to date have no associated biological activity. Fgf14 is expressed in ventral structures of the developing central nervous system. Significantly, unlike other members of the FGF family, Fgf14 also becomes expressed at high levels in the maturing cerebellum in a pattern consistent with localization to granule cells at a time during postnatal development when granule cell migration is ending. The expression pattern and lack of activity towards known FGF receptors suggest that FGF14 may have a novel signaling activity and may be important in the development of physiological function of granule cell neurons. In this proposal we will examine the development and physiological consequences of disrupting these three genes in mice. We will address redundance and cooperativity between Fgfs 8, 17 and 18 and we will investigate other genes that may regulate the expression of these Fgfs or be regulated by them.
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