The overall goal of this project is to elucidate aspects of the genetic control of patterning during histogenesis and foliation in the cerebellum. We have shown that EN-2 mutant mice have specific alterations in the pattern of cerebellum foliation and spinocerebellar afferents, but not in the cytoarchitecture. We have suggested En-2 regulates aspects of cerebellar patterning either by setting up a """"""""pre-pattern"""""""" of parasagittal organization during early embryogenesis or by creating the pattern during the periods of cell differentiation and migration. En-2 is expressed in parasagittal stripes across the cerebellum during embryogenesis, similar to the expression patterns seen at this stage or later for a number of Purkinje cell marker genes. It has been suggested that the early stripe patterns reflect signals that are involved in afferent patterning and/or more general cerebellar patterning. We have made transgenic mice on a En-2 null mutant background that restore En-2 expression in the region that will form the vermis up until approximately 13 days of embryogenesis and found that this does not rescue the foliation defect in the vermis of En-2 null mutants. This indicates that the later expression of En-2 is critical for normal foliation. We have identified two additional genes, Wnt-7b and Pax-2, that are expressed during embryogenesis in stripes complementary to En-2. Furthermore, the Wnt-7b pattern is disrupted in En-2 mutants. By using a combination of genetic and anatomical studies of the roles of the regulatory genes En-2 and Wnt-7b in embryonic and postnatal cellular processes that generate cerebellar pattern will be further studied.
The specific aims are as follows: 1. To address whether En-2 plays multiple roles during development by analyzing the cerebellar phenotypes of conditional En-2 mutants that loose En-2 function at different stages of development. 2. To study the fate of cells expressing En-2 at different times during cerebellar development. 3. To address the genetic mechanism by which the En-genes regulate patterning by analyzing the cerebellar phenotype of transgenic and targeted mice in which the En spatially restricted expression is disrupted. 4. To determine a role for Wnt-7b b cerebellar development by analyzing the cerebellar phenotypes of Wnt-7b mutant mice that lack cerebellar expression of Wnt-7b or express it ectopically. Since the human EN2 gene is also expressed in the fetal cerebellum, our studies should have direct relevance to normal and abnormal processes of cerebellar development in humans.
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