Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency
Abstract
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.
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Progressive axonal swellings along Purkinje cell axons in these mice indicated ongoing dystrophic, neurodegenerative processes.
“In addition, progressive axonal swellings along Purkinje cell axons indicated ongoing dystrophic, neurodegenerative processes.”
From Peroxisomes in brain development and function (2016) · cites this paper as [68]
Purkinje cells in these mice displayed stunted dendrite trees with abnormal branches and spine morphology.
“The Purkinje cells displayed stunted dendrite trees with abnormal branches and spine morphology.”
From Peroxisomes in brain development and function (2016) · cites this paper as [68]
In longer surviving Pex2−/− mice, studies revealed multiple anomalies affecting the interaction of climbing fibers, granule cells and Purkinje cells and, thus, the cerebellar circuitry.
“These studies revealed multiple anomalies affecting the interaction of climbing fibers, granule cells and Purkinje cells and, thus, the cerebellar circuitry.”
From Peroxisomes in brain development and function (2016) · cites this paper as [68]
Disturbed dendritic spine compartmentalization in these mice reflected a delayed arborization and translocation of climbing fibers from the inferior olivary nucleus.
“The disturbed dendritic spine compartmentalization reflected a delayed arborization and translocation of the climbing fibers from the inferior olivary nucleus (the major excitatory input to the Purkinje cells from the caudal medulla).”
From Peroxisomes in brain development and function (2016) · cites this paper as [68]
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Peroxisomes in brain development and function
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“However, because the cerebellum develops largely postnatally in mice, a detailed characterization of cerebellar development was only possible in the longer surviving (Swiss Webster×129Svev) Pex2 mice [68,69].”
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- Authors
- Faust, P. L.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Faust, Phyllis L.
- ORCID
- Faust, Phyllis L.
- Venue
- Journal of Comparative Neurology
- Publisher
- Wiley
- Published
- 2003-05-07
- Volume
- 461
- Issue
- 3
- Pages
- 394-413
- ISSN
- 0021-9967 (ISSN-L)
- 1096-9861
- OpenAlex
- W2051176321
- Cited by
- 71
- References
- 77
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 3 · 2015: 5 · 2014: 3 · 2013: 7 · 2012: 4
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Comparative Neurology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- PEX2, Zellweger syndrome, peroxisome biogenesis disorders, peroxisome deficiency, dendritic spines, axonal swellings, Purkinje cell degeneration, neuronal apoptosis, cerebellar foliation, neuronal migration, neuronal differentiation
- MeSH terms
- Peroxisomal Biogenesis Factor 2, Aging, Animals, Animals, Newborn, Axons, Cell Differentiation, Cell Division, Cell Movement, Cerebellum, Cholesterol 7-alpha-Hydroxylase, Dendrites, Growth Disorders, Immunohistochemistry, Malabsorption Syndromes, Membrane Proteins, Nerve Fibers, Neurons, Olivary Nucleus, Purkinje Cells, Time Factors, Zellweger Syndrome, Cell Death, Mice, Knockout, Peroxisomes, Mice
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