A novel chromosomal mutation has resulted in a strain of mice with developmental, behavioral, and neurological abnormalities. In brief, both males and females are slightly small, highly aggressive mice, in which the cerebrum and olfactory lobes are hypoplastic. This combination of phenotypes is unique, unlike any mouse described in the literature. The long-term goal of this study is to understand the genetic, developmental, biochemical, neuroanatomical, and physiological mechanisms responsible for the extreme aggressive behavior and abnormal brain development in these mice. The immediate goal of the present proposal is to elucidate the genetic basis of the phenotype. The behavior and brain developmental mutation was recovered during a targeting mutagenesis experiment in which a null allele of Zfa (Zinc Finger Locus on Chromosome 10) was derived. These two mutations are linked, but we propose to test the hypothesis that separate strains of mice can be established, each carrying either the Zfa knockout allele or the second mutation. Also, we plan to test the prediction that only the latter strain will display the behavior and brain phenotype. Recently, a genomic deletion was found in these abnormal mice. To test the hypothesis that the deletion is responsible for the behavior and brain phenotype, we will rescue the phenotype with genomic DNA from the deletion. Mapping within this deletion is Mtll, the mouse homologue of the Drosophila tailless gene. We propose to test the hypothesis that Mtll is responsible for the behavior and brain phenotype by creating a conditional """"""""knockout"""""""" of the gene. Finally to test the hypothesis that mutations in the human tailless locus may be important to human mental health, we will map the human tailless gene. We anticipate this work will result in an increased understanding of the genetic basis of aggression and brain development. It will also extend our knowledge of the mammalian tailless gene and explore its role in human diseases. The significance of these studies lies in the ability to draw parallels between what is learned from this mouse model and what is true for human behavior and brain pathologies.
