Granule cell progenitors and their role in cerebellar development: Experimental studies of the math1 null mutant mouse

The rostral rhombic lip of the cerebellum gives rise to the most abundant neuron in the adult CNS, the granule cell. Granule cell precursors undergo a well-characterized temporo-spatial pattern of development that is dependent on both the appropriate expression and function of intrinsic and extrinsic factors (Hatten and Heintz, 1995). Genetic mutations that disrupt this orderly developmental progression result in aberrant cerebellar histogenesis (Goldowitz and Hamre, 1998).In the following studies I examine cerebellar development when the earliest known marker of the granule cell lineage, Math1, is disrupted in both the math1 null and math1 null chimeric cerebellum. I find that granule cell precursors are never generated in the math1 null mutant or chimeric cerebellum, indicating that Math1 has a vital cell intrinsic role in the cerebellar granule cell lineage. In the math1 null chimeric cerebellum I find gaps in the external germinal layer (EGL). The inability of wildtype granule cells to migrate into these regions provides evidence that the tangential migration of granule cell precursors in the formation of the EGL is an active process. I find that in both the complete or partial disruption of the EGL foliation is affected, demonstrating the importance of the EGL in cerebellar foliation. In addition, I find that the complete or partial disruption of the EGL results in Purkinje cell ectopia deep to the cerebellar cortex and the failure of Purkinje cells to align into a single layer, demonstrating the importance of the EGL in Purkinje cell positioning. Finally, I find that 70% of the total Purkinje cell population migrates successfully in the complete absence of the EGL. This finding indicates that the Reelin signal required for the migration of Purkinje cells to the Purkinje cell plate is not solely derived from the EGL, but likely involves signaling from the cells of the nuclear transitory zone.