Evidence of early defects in Cajal-Retzius cell localization during brain development in a mouse model of
H S Booler1, V Pagalday-Vergara1, J L Williams1
1Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Aims:
The secondary dystroglycanopathies represent a heterogeneous group of congenital muscular dystrophies characterized by the defective glycosylation of alpha dystroglycan. These disorders are associated with mutations in at least 17 genes, including Fukutin-related protein (FKRP). At the severe end of the clinical spectrum there is substantial brain involvement, and cobblestone lissencephaly is highly suggestive of these disorders. The precise pathogenesis of this phenotype has, however, remained unclear with most attention focused on the disruption to the radial glial scaffold. Here, we set out to investigate whether lesions are apparent prior to the differentiation of the radial glia.
Methods:
A detailed investigation of the structural brain defects from embryonic day 10.5 (E10.5) up until the time of birth (P0) was undertaken in the Fkrp-deficient mice (FKRPKD ). Reelin, and downstream PI3K/Akt signalling pathways were analysed using Western blot.
Results:
We show that early basement membrane defects and neuroglial ectopia precede radial glial cell differentiation. Furthermore, we identify mislocalization of Cajal-Retzius cells which nonetheless is not associated with any apparent disruption to the reelin, and downstream PI3K/Akt signalling pathways.
Conclusions:
These observations identify Cajal-Retzius cell mislocalization as an early event during the development of cortical defects thereby identifying an earlier onset and more complex pathogenesis than originally reported for the secondary dystroglycanopathies. Overall this study provides new insight into central nervous system involvement in this group of diseases.
Insights
Defects in congenital muscular dystrophies, like those caused by FKRP mutations, begin before radial glia develop. Mislocalized Cajal-Retzius cells indicate an earlier onset of brain abnormalities in these disorders.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Secondary dystroglycanopathies are congenital muscular dystrophies linked to defective alpha-dystroglycan glycosylation.
- Mutations in genes like FKRP contribute to these disorders, often causing severe brain abnormalities and cobblestone lissencephaly.
- The exact cause of brain defects in these conditions, particularly prior to radial glial differentiation, remains unclear.
Purpose of the Study:
- To investigate early brain structural defects in Fkrp-deficient mice.
- To determine if lesions occur before radial glial differentiation in secondary dystroglycanopathies.
- To elucidate the pathogenesis of central nervous system involvement in these disorders.
Main Methods:
- Detailed analysis of brain development in Fkrp-deficient mice from embryonic day 10.5 to birth.
- Assessment of basement membrane integrity and neuroglial cell positioning.
- Western blot analysis of Reelin and PI3K/Akt signaling pathways.
Main Results:
- Early basement membrane defects and neuroglial ectopia were observed before radial glial differentiation.
- Cajal-Retzius cells were mislocalized.
- Reelin and downstream PI3K/Akt signaling pathways showed no apparent disruption despite Cajal-Retzius cell mislocalization.
Conclusions:
- Mislocalization of Cajal-Retzius cells is an early event in cortical defect development for secondary dystroglycanopathies.
- This suggests an earlier onset and more complex pathogenesis than previously understood.
- The study offers new insights into central nervous system involvement in dystroglycanopathies.
