The general focus of Dr. Wynshaw-Boris's laboratory is to understand genetic and biochemical pathways important for the development and function of the mammalian central nervous system. Over the past decade, powerful strategies for the mapping and positional cloning of a number of genes associated with human genetic diseases have been developed, and techniques for manipulating the mammalian genome via transgenic technology have been refined. Wynshaw-Boris and his colleagues have taken advantage of these advances to create and investigate in detail mouse models of human and mammalian genetic diseases that have primary effects in the central nervous system. Their primary goal is to use these models as an entry point to investigate pathways critical for normal brain development and function. However, they also hope that this avenue of investigation will lead to a greater understanding of these diseases, provide novel therapeutic approaches, and provide models to test therapies.

They have created a mouse model for ataxia-telangiectasia (AT), an autosomal recessive disorder characterized by cerebellar degeneration and oculocuteneous telangiectasia, accompanied by immunodeficiency, infertility, small size, sensitivity to the effects of ionizing radiation and increased cancer predisposition. They are analyzing the phenotype of these mice in great detail in order to understand the mechanisms by which a single gene disruption can result in such a pleiotropic phenotype, and to understand pathways which are regulated by Atm.

Dishevelled is one of several segment polarity genes required for the wingless signal transduction pathway in Drosophila. This developmental pathway appears to be conserved in the mouse, where mutations in murine orthologs of this pathway result in a variety of specific abnormalities. Three murine dishevelled genes Dvl1, Dvl2 and Dvl3, have been isolated, and they have made targeted disruptions of all three. Mice homozygous for a null allele of Dvl-1 are viable and fertile, but surprisingly have novel behavioral abnormalities, including abnormal social interaction, depressed startle responses, and sensorimotor gating abnormalities. Thus, Dvl1 mutant mice may provide a model for some aspect of human psychiatric disorders such as schizophrenia or autism. Mice homozygous for a null allele of either Dvl2 or Dvl3 survive to adulthood and are fertile, but are born in reduced numbers from heterozygous or homozygous crosses. In addition, Dvl1/Dvl2 double homozygotes have completely open neural tubes and exencephaly, demonstrating an essential role for Dvl genes in neural tube closure.

Isolated lissencephaly, a dominant human developmental disease characterized by a smooth cerebral surface and incomplete neuronal migration is often associated with small deletions or translocations at chromosome 17p13.3. Miller-Dieker syndrome (MDS) is associated with larger deletions and consists of classical lissencephaly and more complex phenotypes including facial abnormalities. To determine the contribution of various genes on 17p13.3 to MDS, they have created mice with disruptions in various genes in the syntenic region of the mouse (chromosome 11B2) and with deletions spanning the murine MDS critical region using the Cre-loxP system. A similar approach is being used to model DiGeorge (DGS) and related syndromes. These syndromes are associated with deletions and hemizygosity of human chromosome 22q11, and are the result of neural crest migration defects. They hope to study the contribution of single gene disruptions and larger deletions to the phenotypes of these disorders.