Evidence of early defects in Cajal–Retzius cell localization during brain development in a mouse model of dystroglycanopathy

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Type II lissencephaly (also referred to as cobblestone lissencephaly) is a type of neuronal migration disorder highly suggestive of a group of severe congenital muscular dystrophies, characterized by brain, eye and muscle defects. These disorders include Walker–Warburg syndrome (WWS) and Muscle‐Eye‐Brain (MEB) disease, both of which display a range of substantial structural brain abnormalities associated with defects in neuronal migration 1. In addition to type II lissencephaly, WWS and MEB show cortical and cerebellar dysplasia, polymicrogyria and hydrocephalus, with evidence of dysmyelination on MRI 2. Many of these patients characteristically show a marked reduction in the glycosylation of alpha dystroglycan – an extracellular matrix receptor which is a key component of the dystrophin‐associated glycoprotein complex 4. These are now collectively referred to as secondary dystroglycanopathies since they carry mutations in genes involved in the processing of alpha dystroglycan rather than in the gene encoding for dystroglycan itself.
Alpha dystroglycan undergoes extensive O‐mannosylation of its central mucin‐rich domain, and it is these glycan chains that mediate binding to extracellular matrix proteins such as laminin 4, agrin 5, perlecan 8, and neurexin, effectively forming a link between the actin cytoskeleton and the extracellular matrix 9. Altered binding to the extracellular matrix brought about by a reduction in the glycosylation of alpha dystroglycan is considered central to the disease process in the dystroglycanopathies and to date, mutations in 17 putative or determined glycosyltransferase genes have been associated with this group of diseases. These include POMT110, POMT211, POMGNT15, LARGE12, FKTN13, FKRP14, ISPD15, DPM117, DPM218, DPM319, POMK20, GMPPB21, B3GALNT222, GTDC223, TMEM524, B3GNT125 and DOLK27.
Fukutin‐related protein (FKRP) is a putative glycosyltransferase, and mutations in FKRP produce a range of clinical phenotypes from WWS and MEB through to the late‐onset limb girdle muscular dystrophy 2I (LGMD2I). To investigate the pathogenesis of the dystroglycanopathies further, we previously generated a mouse model of dystroglycanopathy which has a deficiency in fukutin‐related protein (FKRPKD). This mouse recapitulates some of the features of MEB; displaying a profound reduction in the glycosylation of alpha dystroglycan at the pial basement membrane, associated with basement membrane defects and a neuronal migration disorder 29. In the dystroglycanopathies, this brain phenotype has been attributed to the inability of the radial glial end feet to maintain integrity of the pial basement membrane during the period of rapid cortical expansion; a process considered central to the neuronal migration defect in these disorders 31.
However, there is now a substantial body of work which suggests that the meninges, traditionally seen as a protective layer covering the brain, play a key role in the production of basement membrane components, retinoic acid and chemotactic factors which are essential for normal corticogenesis 33. Moreover, we have previously identified leptomeningeal disruption in newborn FKRPKD mice 37 potentially implicating the meninges in the pathogenesis of the brain defects associated with the dystroglycanopathies. To further investigate this we have now undertaken a detailed study of FKRPKD mice from E10.5 until P0. These investigations clearly show that basement membrane lesions and neuroglial heterotopia occur prior to radial glial disruption. There is a variation in the time of onset of these lesions, which could account for the range of severity observed at later stages, but lesions were identifiable in all embryos by E11.5. We further show that these defects occur around the time of Cajal–Retzius cell migration, but are not associated with changes in the reelin and downstream PI3K/Akt signalling pathways.
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