CNS DEFECT IN A MURINE ZELLWEGER SYNDROME MODEL

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DESCRIPTION (Verbatim from the Applicant's Abstract): Zellweger syndrome is a human peroxisomal biogenesis disorder that results in abnormal neuronal migrations in the CNS and severe neurologic dysfunction. The principal investigator has developed a murine model for this disorder by targeted deletion of the PEX2 peroxisomal gene and has demonstrated the presence of peroxisomal defects and a cerebral cortical abnormality in newborn mice. PEX2-deficient mice that survive in the postnatal period also develop severe cerebellar abnormalities. In an inbred strain, PEX2 mice appear to develop extensive neuronal lipidosis, with a prominent concentration in the inferior olivary nucleus. These mice provide an important animal model to understand the role of peroxisomal function during CNS development. The principal investigator proposes an integrated series of cellular and molecular studies to begin to answer the following questions. 1. What is the effect of the peroxisomal deficiency on neuronal proliferation, migration, survival, and differentiation during murine CNS development? Neuronal precursor cells will be labeled in vivo with mitotic markers or retroviral infection and their proliferative rate, subsequent migration and final differentiation examined. The investigator will directly visualize the dynamics of migrating neurons in vitro by video microscopy using cultured brain slices. The architectural changes that occur in the mutant brains will be examined with cell type specific markers having established developmental patterns to define the onset and the evolution of the peroxisomal disease process. Ultrastructural studies will define further the cell type specific peroxisomal pathology observed at various stages of development. The effect of peroxisomal deficiency on neuronal survival and postmigratory differentiation will be examined. 2. What is the role of cell autonomous function versus epigenetic factors in causing the developmental defects? Two major strategies will be used to approach this question and include: a. in vivo transplantation of normal or peroxisome-deficient neuronal progenitors into normal or mutant developing cortex. These studies will evaluate whether the cellular defects observed in the brain of peroxisome deficient neurons are intrinsic to the neurons versus secondary to defects in other brain cells and/or environmental alterations; and b. liver/gut specific PEX2 transgene expression to correct hepatic peroxisomal abnormalities and evaluate the role of circulating toxic factors and/or malnutritions that result from hepatic dysfunction versus intrinsic brain metabolism in causing the CNS defects.