Neocortical and cerebellar developmental abnormalities in conditions of selective elimination of peroxisomes from brain or from liver
Abstract
Defects in the formation of the cerebral cortex and the cerebellum are a prominent feature of the peroxisome biogenesis disorder Zellweger syndrome and in mouse models for this disease. The aim of the present study was to investigate the impact of liver and brain peroxisomes on neurodevelopment by analyzing mice with tissue-selective elimination of peroxisomes. To this end, Pex5-loxP mice were bred with albumin/alpha-fetoprotein (Alfp)-Cre and nestin (Nes)-Cre mice. Local elimination of peroxisomes from the brain in Nes-Pex5 knockout mice caused a delay of cortical neuronal migration and of the formation of cerebellar folia and fissures. Migration of granule cells from the external granular layer was retarded, as was the polarization and branching of Purkinje cells, resulting in a less complex branching pattern and a smaller dendritic tree at P21. The Alfp-Pex5 knockout mice were affected differently, displaying a partial arrest of neuronal migration in the cerebral neopallium in the postnatal period despite of the incomplete elimination of peroxisomes from liver during embryonic development. Major abnormalities were seen in the formation of the cerebellum of these liver knockout mice, including hypotrophy, impaired foliation, a delay of granule cell migration, increased cell death, and stunted Purkinje cell arborization. In conclusion, these data demonstrate that absence of peroxisomal function both from liver and brain impairs cortical neuronal migration and maturation of the cerebellum, but different pathogenic mechanisms might be involved.
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A NEX promoter-driven Pex5 KO showed that the lack of peroxisomes in neurons did not lead to VLCFA accumulation or brain dysfunction.
“Another neuronal helix–loop–helix protein (NEX) promoter-driven Pex5 KO showed that the lack of peroxisomes in neurons did not lead to VLCFA accumulation or brain dysfunction, while another glial fibrillary acidic protein (GFAP) promoter-driven Pex5 KO showed that the lack of peroxisomes in astrocytes, despite causing VLCFA accumulation, had no significant impact on CNS functioning [264,266].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [266]
A GFAP promoter-driven Pex5 KO showed that the lack of peroxisomes in astrocytes, despite causing VLCFA accumulation, had no significant impact on CNS functioning.
“Another neuronal helix–loop–helix protein (NEX) promoter-driven Pex5 KO showed that the lack of peroxisomes in neurons did not lead to VLCFA accumulation or brain dysfunction, while another glial fibrillary acidic protein (GFAP) promoter-driven Pex5 KO showed that the lack of peroxisomes in astrocytes, despite causing VLCFA accumulation, had no significant impact on CNS functioning [264,266].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [266]
Selective loss of peroxisomal functions in hepatocytes of the liver (α-fetoprotein-Cre) results in brain abnormalities including defects in cerebral neuronal migration and cerebellar development.
“However, also the selective loss of peroxisomal functions in hepatocytes of the liver, obtained by α-fetoprotein-Cre driver mice [72], results in brain abnormalities including defects in cerebral neuronal migration and cerebellar development (hypotrophy, increased apoptosis, immature foliation, delayed granule cell migration and stunted Purkinje cells).”
From Peroxisomes in brain development and function (2016) · cites this paper as [72]
Nestin-Pex5−/− mice show postnatally delayed cerebellar development including immature foliation and dendritic arborization of Purkinje cells.
“postnatally, delayed cerebellar development including immature foliation and dendritic arborization of Purkinje cells [72].”
From Peroxisomes in brain development and function (2016) · cites this paper as [72]
In the developing brain of Nestin-Pex5−/− mice, a defect in neuronal layer formation in the cerebral cortex indicates neuronal migration defects.
“In the developing brain, a defect in neuronal layer formation in the cerebral cortex was observed indicative of neuronal migration defects”
From Peroxisomes in brain development and function (2016) · cites this paper as [72]
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References 43 · Cited by 90
- Authors
- Krysko, O., Hulshagen, L., Janssen, A., Schütz, G., Klein, R., De Bruycker, M., Espeel, M., Gressens, P., & Baes, M.
- Affiliations
- KU Leuven (BE)
- German Cancer Research Center (DE)
- Max Planck Society (DE)
- Ghent University (BE)
- Corresponding author
- Baes, Myriam
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2006-10-30
- Volume
- 85
- Issue
- 1
- Pages
- 58-72
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2053095537
- Cited by
- 90
- References
- 43
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 5 · 2019: 2 · 2018: 6 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 7 · 2012: 3
- FWCI
- 1.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- 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
- Zellweger syndrome, peroxisome biogenesis disorders, PEX5, cerebellar development, granule cell migration, cerebellar foliation, liver peroxisomes, conditional knockout mice, brain development
- MeSH terms
- Peroxisome-Targeting Signal 1 Receptor, Age Factors, Animals, Brain Chemistry, Cell Movement, Cerebellum, Deoxyadenine Nucleotides, Disease Models, Animal, Embryo, Mammalian, Female, Immunohistochemistry, Liver, Male, Mice, Inbred C57BL, Neurons, Pregnancy, RNA, Messenger, Blotting, Northern, Zellweger Syndrome, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Neocortex, Reverse Transcriptase Polymerase Chain Reaction, Peroxisomes, Microscopy, Electron, Transmission, Mice
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