Related Experiment Video
Updated: Apr 5, 2026
Induction of Protein Deletion Through In Utero Electroporation to Define Deficits in Neuronal Migration in Transgenic Models
Published on: January 12, 2015
Degree of Cajal-Retzius Cell Mislocalization Correlates with the Severity of Structural Brain Defects in Mouse Models
Helen S Booler1, Josie L Williams1, Mark Hopkinson1
1Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Abstract:
The secondary dystroglycanopathies are characterized by the hypoglycosylation of alpha dystroglycan, and are associated with mutations in at least 18 genes that act on the glycosylation of this cell surface receptor rather than the Dag1 gene itself. At the severe end of the disease spectrum, there are substantial structural brain defects, the most striking of which is often cobblestone lissencephaly. The aim of this study was to determine the gene-specific aspects of the dystroglycanopathy brain phenotype through a detailed investigation of the structural brain defects present at birth in three mouse models of dystroglycanopathy-the FKRP(KD) , which has an 80% reduction in Fkrp transcript levels; the Pomgnt1null , which carries a deletion of exons 7-16 of the Pomgnt1 gene; and the Large(myd) mouse, which carries a deletion of exons 5-7 of the Large gene. We show a rostrocaudal and mediolateral gradient in the severity of brain lesions in FKRP(KD) , and to a lesser extent Pomgnt1null mice. Furthermore, the mislocalization of Cajal-Retzius cells is correlated with the gradient of these lesions and the severity of the brain phenotype in these models. Overall these observations implicate gene-specific differences in the pathogenesis of brain lesions in this group of disorders.
Insights
Secondary dystroglycanopathies cause brain defects due to alpha dystroglycan hypoglycosylation. Mouse models reveal gene-specific brain lesion patterns and Cajal-Retzius cell mislocalization, impacting disease severity.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Secondary dystroglycanopathies involve alpha dystroglycan hypoglycosylation.
- Mutations in over 18 genes, excluding Dag1, cause these disorders.
- Severe cases present with significant structural brain defects, including cobblestone lissencephaly.
Purpose of the Study:
- To investigate gene-specific brain phenotypes in dystroglycanopathies.
- To analyze structural brain defects at birth in mouse models.
- To understand the relationship between gene mutations and brain malformations.
Main Methods:
- Utilized three mouse models: FKRP(KD), Pomgnt1null, and Large(myd).
- Examined structural brain defects present at birth.
- Assessed the rostrocaudal and mediolateral gradient of brain lesions.
- Correlated Cajal-Retzius cell mislocalization with lesion severity.
Main Results:
- Observed a rostrocaudal and mediolateral gradient of brain lesion severity in FKRP(KD) and Pomgnt1null mice.
- Demonstrated that Cajal-Retzius cell mislocalization correlates with lesion gradients.
- Highlighted gene-specific differences in the severity and pattern of brain defects.
Conclusions:
- Gene-specific variations contribute to the pathogenesis of brain lesions in dystroglycanopathies.
- The study provides insights into the molecular mechanisms underlying brain malformations in these disorders.
- Understanding these gene-specific aspects is crucial for developing targeted therapies.
