Genetic influences on the migration of cerebellar granule cells and on the development of cerebellar folia

Abstract

A comparison of the cerebellar cortex of BALB/cByJ and C57BL/6J mice showed two morphological differences. First, the BALB/cByJ progenitor strain have a high number of ectopic granule cells (145.8 ± 8.7 per section), whereas the C57BL/6J progenitor strain have a low number (36.0 ± 1.0 per section). Second, BALB/cByJ mice have a secondary fissure which subdivides the uvulovermal lobule. The CXB set of recombinant inbred strains, originally derived using BALB/c and C57BL/6 as progenitor strains, was used to determine the genetic influences on the production of ectopic granule cells and on cerebellar foliation and to determine their relationship to each other. Of the seven recombinant inbred strains, five (CXBD, CXBG, CXBH, CXBI, and CXBK) have BALB/c-like numbers of ectopic granule cells and two (CXBE and CXBJ) had C57BL/6-like numbers of ectopic granule cells. Small clusters of ectopic granule cells located at the pial surface are found in BALB/cByJ and in all five of the recombinant inbred strains with BALB/c-like granule cell ectopia. The fact that the strain distribution patterns for both the granule cell ectopia and the presence of small ectopic granule cell clusters are concordantwith the strain distribution pattern for the Hid locus, a single autosomal dominant gene that affects the lamination of hippocampal area CA3c, indicate thatHW has pleiotropic effects on both cerebellar and hippocampal development. The strain distribution pattern for the presence of the secondary fissure in the uvulovermal lobule is non-concordant with the strain distribution pattern for the Hid locus. In addition, secondary fissures not characteristic of either progenitor strain are found in some of the CXB strains, and two recombinant inbred strains (CXBD and CXBG) have large clusters of ectopic granule cells and ectopic Purkinje cells. Thus, this study has identified three different aspects of cerebellar development that are under distinct genetic control: 1) the presence of ectopic granule cells and small clusters of ectopic granule cells, both of which may be pleiotropic effects ofHid, 2) the presence of large clusters of ectopic granule cells and ectopic Purkinje cells, and 3) the pattern of cerebellar foliation. These findings demonstrate that inbred and recombinant inbred strains are useful for the elucidation of developmental genetic relationships between diverse regions of the CNS.