Trisomy of chromosome 21 is the major genetic cause of intellectual disability, collectively known as Down syndrome (DS), and occurs in 1 in 800 live birth in Japan. The neuropathology of DS suggests that the gross brain pathology is associates with the specific profile of working memory and/or verbal short-term memory. These pathophysiological changes of DS also include the changes in size of specific brain regions and their connectivity and alternations in the number and/or the morphology of a certain population of neurons. In a past decade, the candidate genes and their interactions have been explored, however, the whole picture of pathological process of DS has not been revealed. Here, we report that a down syndrome-associated gene regulates the neuronal migration and eventual distribution. Reducing the expression of this gene by short-hairpin RNAs or in mutant mice showed the aberrant migration, including the arresting or backward movement. Overexpression of this protein in wild-type mice, which is induced by in utero electropolation, caused the mis-directional projection of leading process, and uneven final distribution. Several studies in DS fetal brain and in the trisomy mouse, which express this protein at higher level, have reported the reduction in the brain volume and cell number in the hippocampus and cerebellum. Consistently, we found that the number of neurons in mutant mice, which express this protein at lower level, was increased. We will discuss the functional role of this gene in the pathogenesis of DS.