Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency.
The form and circuitry of the cerebellum develops by a complex process that requires integration of afferent-target interactions between multiple neuronal populations and migratory patterns established by neuron-glial interactions. Analysis of mice lacking the PEX2 peroxisome assembly gene, in which peroxisomal function is disrupted, reveals abnormal cerebellar histogenesis due to the disturbance of multiple cellular processes within neurons. Defects in cerebellar growth and the rostro-caudal foliation pattern reflect a reduced granule neuron population and abnormal Purkinje cell dendrite development. In granule neurons, there is increased apoptotic cell death and delayed movement from the EGL to IGL that reflects cell cycle, maturational and migrational abnormalities. The underlying Purkinje cells have stunted dendrite arbors with abnormal branching patterns, which may reflect altered inductive influences from the delayed granule neuron translocation. A delayed arborization of mutant olivary climbing fibers and their defective translocation from the perisomatic to the dendritic compartment of Purkinje cells results in numerous spines on the soma and proximal dendrites of Purkinje cells. Distal Purkinje cell dendritic spines also display abnormal morphology. These Purkinje cell dendritic abnormalities are seen in association with persistent and enlarged axonal spheroids, further indicating the presence of a degenerative process within the Purkinje cell. This PEX2(-/-) mouse model for the human peroxisomal biogenesis disorder Zellweger syndrome illustrates the complex interplay of abnormal developmental processes in the cerebellum and the importance of peroxisomal function for neuronal migration, proliferation, differentiation, and survival.
Department of Pathology, Columbia University, New York, New York 10032, USA. plf3@columbia.edu
Phyllis L
PL
Faust
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development / Q000502:physiology; D001369:Axons / Q000473:pathology; D016923:Cell Death; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D002531:Cerebellum / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics; D003712:Dendrites / Q000648:ultrastructure; D006130:Growth Disorders / Q000209:etiology; D007150:Immunohistochemistry; D008286:Malabsorption Syndromes / Q000209:etiology / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009412:Nerve Fibers / Q000648:ultrastructure; D009474:Neurons / Q000473:pathology* / Q000502:physiology; D009847:Olivary Nucleus / Q000473:pathology; D000074428:Peroxisomal Biogenesis Factor 2; D020675:Peroxisomes / Q000473:pathology*; D011689:Purkinje Cells / Q000166:cytology / Q000648:ultrastructure; D013997:Time Factors; D015211:Zellweger Syndrome / Q000150:complications / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology
D008565:Membrane Proteins; C000614230:PEX2 protein, human; C000614231:PEX2 protein, mouse; D000074428:Peroxisomal Biogenesis Factor 2; D002790:Cholesterol 7-alpha-Hydroxylase