Analysis of Cerebellar Development in math1 Null Embryos and Chimeras

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 is math1. In the math1 null mouse, neuroblasts never populate the external germinal layer (EGL) that gives rise to granule cells. In this study, we examined the embryonic development of the math1 null cerebellum and analyzed experimental mouse chimeras made from math1 null 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 that math1 null granule cells are absent in the math1 null 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.