ANALYSIS OF GENE-ACTION IN THE MEANDER TAIL MUTANT MOUSE - EXAMINATION OF CEREBELLAR PHENOTYPE AND MITOTIC-ACTIVITY OF GRANULE CELL NEUROBLASTS

The meander tail (mea) gene results in a stereotypic pattern of cerebe llar abnormalities, most notably the virtual depletion of granule cell s in the anterior lobe of the cerebellum. The causal basis of this mut ation is unknown. In this paper we have taken a three-part approach to the analysis of mea gene action. First, we quantitatively determined the effect of the mea gene on granule cell and Purkinje cell number. W e found, in addition to the marked depletion of anterior lobe granule cells (> 90%), there were also significantly fewer granule cells in th e posterior lobe (20-30%) without a concomitant loss of Purkinje cells . Second, we explored the relationship between granule cell depletion caused by the mea gene and by the mitotic poison, 5-fluoro-2'-deoxyuri dine (FdU). Prenatal and postnatal ICR mice were treated with FdU to a scertain the regimen that best produces a meander tail-like cerebellar phenotype. The similarity of the effects of the mea gene and injectio ns of FdU at E17 and PO suggests the hypothesis that the mea gene acts to disrupt the cell cycle of cerebellar granule cell precursors. Thus , the third part of this study was to test this hypothesis by using in jections of either BrdU (5-bromo-2'-deoxyuridine) or H-3-thymidine int o homozygous and heterozygous meander tail littermates at E17 or P0. A fter processing the tissue for BrdU immunocytochemistry or H-3-thymidi ne autoradiography, counts were made of the number of labeled and unla beled external granule layer (EGL) cells to determine the percentage t hat had incorporated the mitotic label (labeling index). No difference in the labeling index was found between homozygous meander tail mice and normal, heterozygous littermate controls. Therefore, the mitotic a ctivity of the EGL neuroblasts is not disrupted by the mea gene. Furth ermore, while a mitotic poison can produce a phenotype similar to the action of the mea gene, mea is phenomenologically different from FdU t reatment. (C) 1996 Wileg-Liss, Inc.