445. Cyclooxygenase and brain development: implications in Rett’s syndrome

Abstract

Cyclooxygenase (COX)-2, the inducible form of COX known for its role in prostanoid biosynthesis, belongs to a subset of genes localized to dendritic spines that are regulated by synaptic activity. Altered COX-2 expression in dendrites of brains of cases affected by Rett’s syndrome, a form of profound psychomotor retardation, has been reported. Thus alteration of neuronal COX-2 may play an important role in abnormal development and possibly in mechanism leading to mental retardation. To further explore the role of COX-2 in brain, we generated a transgenic mouse model with neuronal overexpression of human (h)COX-2 and used DNA microarray techniques to identify clusters of gene differentially expressed in brain of COX-2 transgenics. Because the genes screened in the DNA microarray were clustered by an algorithm designed to group genes into functional families we were able to identify a pattern of changes within distinct biochemical hierarchies that were affected by COX-2 overexpression. Data from this analysis indicated that genes involved in cell cycle/division (cycle dependent kinase, CDK-1) and cell growth (glial derived growth factor, GDNF) are affected in brain of COX-2 transgenics. The result of the analysis suggests that COX-2 may play important role in brain development. We hypothesize that COX-2 expression may indirectly influence the mechanism involved in abnormal dendritic development in Rett’s syndrome.