The purpose of this project is to study molecular mechanisms of brain development by defining the underlying changes in gene expression. Our mode system is the murine cerebellum. By cloning genes whose expression is regulated during cerebellar development, we identify genes potentially involved in specific aspects of this process. To determine conclusively the function of these genes, they will be mutated in embryonic stem cells and the phenotypes of mice carrying the mutant alleles will be assessed. In a screen of 80,000 cDNA clones from a postnatal day 10 (P10) cerebellum (cbm) library, we identified 6 novel cDNA clones whose expression decreases drastically from embryonic day 18 (E18) to adult. Surprisingly, we identified no clones whose expression was higher at P10 than at E18. These results suggest the coordinate shut-down of a class of developmentally significant genes in the early postnatal period. The cell types expressing these genes are being investigated by in situ hybridization to sections of developing brain. We have established the embryonic stem cell - transgenic system in our lab to analyze the effect of mutating these genes. Chimeric mice have been made by injection of embryonic stem cells into blastocysts. Understanding the processes involved in normal brain development will give us important keys in understanding the relationships between development an mental performance as well as aberrant development and mental illness.
