Down syndrome (DS) is the most common genetic cause of mental retardation and in most cases is due to three full copies of human chromosome 21 (HC21). Mental retardation in DS is probably a consequence of the anomalous development of the central nervous system, so genes which show temporal or high levels of expression during the development of the central nervous system may be of special importance in DS, especially in the pathogenesis of mental retardation. Recently, the human homologue of the Drosophila minibrain gene was isolated from HC21. Its location, together with its probable function in neurogenesis, supports MNB as a strong candidate gene to produce some of the neurological abnormalities present in DS patients. To determine the biological function of MNB, I propose to knockout the gene in mouse and to assess the contribution of MNB dysfunction to the abnormal brain development and mental retardation observed in DS.