Analysis of Cerebellar Development inmath1Null Embryos and Chimeras

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Abstract
The cerebellar granule cell is the most numerous neuron in the nervous system and likely the source of the most common childhood brain tumor, medulloblastoma. The earliest known gene to be expressed in the development of these cells ismath1. In themath1null mouse, neuroblasts never populate the external germinal layer (EGL) that gives rise to granule cells. In this study, we examined the embryonic development of themath1null cerebellum and analyzed experimental mouse chimeras made frommath1null embryos. We find that the anterior rhombic lip gives rise to more than one cell type, indicating that the rhombic lip does not consist of a homogeneous population of cells. Furthermore, we demonstrate thatmath1null granule cells are absent in themath1null chimeric cerebellum, from the onset of their genesis in the mouse anterior rhombic lip. This finding indicates a vital cell intrinsic role for Math1 in the granule cell lineage. In addition, we show that wild-type cells are unable to compensate for the loss of mutant cells. Finally, the colonization of the EGL by wild-type cells and the presence of acellular gaps provides evidence that EGL neuroblasts undergo active migration and likely have a predetermined spatial address in the rhombic lip.