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Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder.

Faust PL, Hatten ME - J. Cell Biol. (1997)

Bottom Line: The mutant animals do not feed and are hypoactive and markedly hypotonic.They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens.Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar-lipid inclusions.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York 10021, USA. plf3@columbia.edu

ABSTRACT
Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2-deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2-deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar-lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease.

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Immunofluorescence staining of forebrain and cerebellum. (A) Coronal section of E15 forebrain from PEX2 mutant  mouse stained with RC2 antibody to label the radial glia. (B and  C) Saggital section of P0 cerebellum from PEX2 mutant mouse  stained with calbindin-D28k antibody to label the Purkinje cells  (PCs). Anterior is to the left. Arrow indicates small cluster of bipolar PCs slightly beneath the multilayer, shown at higher power  in C, indicating a slight delay in the migration of these PCs. Images in A and C were obtained by confocal microscopy. Bars: (A  and C) 50 μm; (B) 100 μm.
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Figure 5: Immunofluorescence staining of forebrain and cerebellum. (A) Coronal section of E15 forebrain from PEX2 mutant mouse stained with RC2 antibody to label the radial glia. (B and C) Saggital section of P0 cerebellum from PEX2 mutant mouse stained with calbindin-D28k antibody to label the Purkinje cells (PCs). Anterior is to the left. Arrow indicates small cluster of bipolar PCs slightly beneath the multilayer, shown at higher power in C, indicating a slight delay in the migration of these PCs. Images in A and C were obtained by confocal microscopy. Bars: (A and C) 50 μm; (B) 100 μm.

Mentions: To examine the radial glial scaffold, which serves as the guidance substrate for cortical neuronal migration, brains from E15 mice were stained with antibodies against RC2 and brain lipid binding protein (BLBP), both markers for radial glia (Misson et al., 1988; Feng et al., 1994). RC2 and BLBP immunostains showed no obvious abnormality in the radial glial scaffold in brains from homozygous PEX2-deficient mice (Fig. 5 A; BLBP not shown).


Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder.

Faust PL, Hatten ME - J. Cell Biol. (1997)

Immunofluorescence staining of forebrain and cerebellum. (A) Coronal section of E15 forebrain from PEX2 mutant  mouse stained with RC2 antibody to label the radial glia. (B and  C) Saggital section of P0 cerebellum from PEX2 mutant mouse  stained with calbindin-D28k antibody to label the Purkinje cells  (PCs). Anterior is to the left. Arrow indicates small cluster of bipolar PCs slightly beneath the multilayer, shown at higher power  in C, indicating a slight delay in the migration of these PCs. Images in A and C were obtained by confocal microscopy. Bars: (A  and C) 50 μm; (B) 100 μm.
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Related In: Results  -  Collection

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Figure 5: Immunofluorescence staining of forebrain and cerebellum. (A) Coronal section of E15 forebrain from PEX2 mutant mouse stained with RC2 antibody to label the radial glia. (B and C) Saggital section of P0 cerebellum from PEX2 mutant mouse stained with calbindin-D28k antibody to label the Purkinje cells (PCs). Anterior is to the left. Arrow indicates small cluster of bipolar PCs slightly beneath the multilayer, shown at higher power in C, indicating a slight delay in the migration of these PCs. Images in A and C were obtained by confocal microscopy. Bars: (A and C) 50 μm; (B) 100 μm.
Mentions: To examine the radial glial scaffold, which serves as the guidance substrate for cortical neuronal migration, brains from E15 mice were stained with antibodies against RC2 and brain lipid binding protein (BLBP), both markers for radial glia (Misson et al., 1988; Feng et al., 1994). RC2 and BLBP immunostains showed no obvious abnormality in the radial glial scaffold in brains from homozygous PEX2-deficient mice (Fig. 5 A; BLBP not shown).

Bottom Line: The mutant animals do not feed and are hypoactive and markedly hypotonic.They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens.Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar-lipid inclusions.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York 10021, USA. plf3@columbia.edu

ABSTRACT
Zellweger syndrome is a peroxisomal biogenesis disorder that results in abnormal neuronal migration in the central nervous system and severe neurologic dysfunction. The pathogenesis of the multiple severe anomalies associated with the disorders of peroxisome biogenesis remains unknown. To study the relationship between lack of peroxisomal function and organ dysfunction, the PEX2 peroxisome assembly gene (formerly peroxisome assembly factor-1) was disrupted by gene targeting. Homozygous PEX2-deficient mice survive in utero but die several hours after birth. The mutant animals do not feed and are hypoactive and markedly hypotonic. The PEX2-deficient mice lack normal peroxisomes but do assemble empty peroxisome membrane ghosts. They display abnormal peroxisomal biochemical parameters, including accumulations of very long chain fatty acids in plasma and deficient erythrocyte plasmalogens. Abnormal lipid storage is evident in the adrenal cortex, with characteristic lamellar-lipid inclusions. In the central nervous system of newborn mutant mice there is disordered lamination in the cerebral cortex and an increased cell density in the underlying white matter, indicating an abnormality of neuronal migration. These findings demonstrate that mice with a PEX2 gene deletion have a peroxisomal disorder and provide an important model to study the role of peroxisomal function in the pathogenesis of this human disease.

Show MeSH
Related in: MedlinePlus