Embryonic Development of the Cerebellum

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DESCRIPTION (provided by applicant): Our previous work has focused on the specification of granule cells in the embryonic cerebellum. Here we wish to turn our attention to the other principal neuron of the cerebellum, the Purkinje cell and to the deep neurons. The overall aim of this project is to determine the topographic expression of four classes of transcription factors, LIM homeodomain genes (Lhx1, Lhx3, Lhx5, and Lhx9), basic helix-loop-helix genes (Math1, Mash1, Ngn1, Ngn2), Paired box containing genes (Pax2) and Even-Skipped genes (Evx1,2) in Purkinje and deep neuron progenitor cell populations in the embryonic cerebellar primordium, and to use these markers to examine factors that shape cell fate specification. The action of local inductive factors, BMPs on gene expression and cell specification patterning will be tested in gene expression studies in the chick embryo and in the Dreher mutant mouse.First, we will define patterns of gene expression in murine and avian embryos focusing on the time periods when deep neurons and Purkinje cells are generated. We will further refine our analysis by studying BAC transgenic mice for Lhx1, Lhx3, Lhx5, Lhx9, Math1, Mash1, Ngn1, Ngn2 and Evx1 generated in another project. Second, we will study the Dreher mutant mouse, because it suffers a loss of BMPs, and use in ovo electroporation in avian embryos to define the role of BMP6, BMP7 and GDF7 in transcription factor expression patterns. Finally, we will study the function of these transcription factors in cerebellar cell differentiation by analyzing mice with targeted null mutations and by transfecting morpholino antisense oligonucleotides into avian embryos.