Down Syndrome (DS) is a major cause of mental retardation that results from trisomy of chromosome 21 (Lejeune, Gautier et al. 1959), and consequently, abnormally elevated dosages of genes located within this chromosome. DS patients have stereotyped facial and physical malformations, congenital heart and gut disease, as well as, complications within the immune and endocrine systems, as well as an increased risk of leukemia and Alzheimer’s disease. Among this constellation of symptoms, DS is most closely associated with cognitive deficits that arise from a complex cortical phenotype. Human postmortem studies have shown that cortical size and thickness are reduced and lamination is disrupted in the brains of DS patients (Jernigan and Bellugi 1990; Jernigan, Bellugi et al. 1993; Golden and Hyman 1994). The numbers of layer IV neurons are depleted and dendritic spines reduced in the DS cortex (Ross, Galaburda et al. 1984; Takashima, Ieshima et al. 1989). DSCAM (Down Syndrome Cell Adhesion Molecule) maps to the particular region within chromosome 21 that is sufficient to induce cognitive deficits (Antonarakis 1998; Yamakawa, Huot et al. 1998). DSCAM belongs to the immunoglobulin (Ig) superfamily of cell adhesion molecules and mediates homophilic intracellular adhesion (Agarwala, Nakamura et al. 2000). Members of the Ig superfamily mediate cellular adhesion and neurite extention. Given the activities of DSCAM family members, we hypothesize that DSCAM is required for proper neural migration, morphological differentiation, and axonal targeting. Precise interactions between adhesion molecules provide a mechanism by which neurons can be guided to their final positions in the cortex and be connected to each other within an intricate network. By determining how the overexpression of DSCAM contributes to the cognitive pathology of DS and conducting loss-of-function studies in parallel, we will learn more about the way in which DSCAM directs normal cortical development.

Our Specific Aims will be to: (1) Establish RNA expression patterns and subcellular protein localization of endogenous DSCAM and DSCAML1 throughout corticogenesis and; (2) to determine mechanisms responsible for the cortical perturbations associated with Down syndrome, as well as normal development, by overexpressing full-length and truncated forms of DSCAM and DSCAML1 in the developing cortex by in utero electroporation.