Abstract
Aberrant glycosylation of dystroglycan causes congenital muscular dystrophies associated with cobblestone lissencephaly, classified as dystroglycanopathy. However, pathological features in the onset of brain malformations, including the precise timing and primary cause of the pial basement membrane disruption and abnormalities in the migration of pyramidal neurons, remain unexplored. Using the Pomgnt2-knockout (KO) mouse as a dystroglycanopathy model, we show that breaches of the pial basement membrane appeared at embryonic day 11.5, coinciding with the ectopic clustering of Cajal–Retzius cells and subplate neurons and prior to the migration onset of pyramidal neurons. Furthermore, in the Pomgnt2-KO cerebral cortex, preplate splitting failure likely occurred due to the aggregation of Cajal–Retzius and subplate cells, and migrating pyramidal neurons lost polarity and radial orientation. Our findings demonstrate the initial pathological events in dystroglycanopathy mice and contribute to our understanding of how dystroglycan dysfunction affects brain development and progresses to cobblestone lissencephaly.
Highlights
The ligand-binding glycan expressed on dystroglycan is a unique phosphodiester-linked polysaccharide structure built on the O-mannose attached to the dystroglycan core protein, which is known as the so-called post-phosphoryl modification[8]
These findings reveal the final outcome of brain defects in dystroglycanopathy and suggest that the abnormalities are derived as a secondary defect of neuronal migration due to the dysfunction of radial glial cells
It remains unclear whether the pial basement membrane disruption in dystroglycanopathy is caused by migrating pyramidal neurons or other pathological events
Summary
The ligand-binding glycan expressed on dystroglycan is a unique phosphodiester-linked polysaccharide structure built on the O-mannose attached to the dystroglycan core protein, which is known as the so-called post-phosphoryl modification[8]. The neuron-specific depletion of dystroglycan in mice causes no overt pathological changes in brain architecture[23], indicating that the neuronal migration defect may be caused by environmental changes, and not by an alteration of the neuron itself. These findings reveal the final outcome of brain defects in dystroglycanopathy and suggest that the abnormalities are derived as a secondary defect of neuronal migration due to the dysfunction of radial glial cells. Our findings contribute to the understanding of initial pathological events in the developing brain of the dystroglycanopathy mouse model, which lead to cobblestone lissencephaly
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
