Phyllis L. Faust, M.D., Ph.D.

Research in this laboratory is aimed at gaining a better understanding of human brain malformations in which there is an abnormality in neuronal migration. We have initiated studies on peroxisomal biogenesis disorders, which includes several neonatal and childhood diseases that result from a lack of normal peroxisomal function. Zellweger syndrome is the most severe phenotype and results in abnormal neuronal migrations in the central nervous system and severe neurologic dysfunction. In the central nervous system, the disordered neuronal migration leads to characteristic cytoarchitectonic abnormalities involving the cerebral hemispheres, the cerebellum and inferior olivary complex. We have created a mouse model for Zellweger syndrome by targeted deletion of the peroxisomal PEX2 gene, shown to be linked to this disorder in humans. Homozygous PEX2-deficient mice lack normal peroxisomes and have biochemical abnormalities characteristic of peroxisomal deficiency. In the brain of newborn mutant mice, there is disordered lamination of the cerebral cortex and an increased neuronal cell density in the underlying white matter, indicating an abnormality of neuronal migration. In older surviving PEX2 mutant mice, there is abnormal cerebellar development with abnormalities in foliation and Purkinje cell dendritic development. This mouse model can serve as a system to elucidate the role of peroxisomal function in the many steps required for nervous system development, including cell proliferation/cell death, neuronal migration and differentiation.

The central nervous system abnormalities that occur in PEX2 mutant mice will be further characterized by a variety of techniques including: 1) Morphologic studies with light and electron microscopy, immunohistochemistry, birthdating analysis and in situ hybridization; 2) Lineage tracing during cortical development using retroviral vectors to examine the behavior of small clones of neurons; 3) Cell transplantation studies into normal and mutant mouse brains utilizing isolated neuronal progenitor cells; 4) Video-microscopic analysis of migration in brain slices in vitro. Murine models for other peroxisomal diseases can also be created by gene targeting as several new genes linked to these disorders have been recently described.

Selected Publications:

• Faust, P.L., and Hatten, M.E. Production of a Mouse Model for Zellweger Syndrome, a Neuronal Migration Disorder. J. Neuropath. Exp. Neuro. 55: 630. (1996).

• Faust, P.L., and Hatten, M.E. Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder. J. Cell Biol. 139: 1293-1305 (1997).

• Pearlman, A.L., Faust, P.L., Hatten, M.E., and Brunstrom, J.E. New directions for neuronal migration. Curr. Opinion Neurobiol. 8: 45-54 (1998).