Abstract
BackgroundCobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD. In these severe forms of dystroglycanopathy, the muscular dystrophy and other tissue pathology is caused by mutations in genes involved in O-linked glycosylation of alpha-dystroglycan. While cerebellar dysplasia is a common feature of dystroglycanopathy, its pathogenesis has not been thoroughly investigated.ResultsHere we evaluate the role of dystroglycan during cerebellar development. Brain-selective deletion of dystroglycan does not affect overall cerebellar growth, yet causes malformations associated with glia limitans disruptions and granule cell heterotopia that recapitulate phenotypes found in dystroglycanopathy patients. Cerebellar pathology in these mice is not evident until birth even though dystroglycan is lost during the second week of embryogenesis. The severity and spatial distribution of glia limitans disruption, Bergmann glia disorganization, and heterotopia exacerbate during postnatal development. Astrogliosis becomes prominent at these same sites by the time cerebellar development is complete. Interestingly, there is spatial heterogeneity in the glia limitans and granule neuron migration defects that spares the tips of lobules IV-V and VI.ConclusionsThe full spectrum of developmental pathology is caused by loss of dystroglycan from Bergmann glia, as neither granule cell- nor Purkinje cell-specific deletion of dystroglycan results in similar pathology. These data illustrate the importance of dystroglycan function in radial/Bergmann glia, not neurons, for normal cerebellar histogenesis. The spatial heterogeneity of pathology suggests that the dependence on dystroglycan is not uniform.
Highlights
Cobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD
Dystroglycan is expressed in Purkinje cells (PCs) during early postnatal cerebellar development [21], and DGpositive puncta rimmed the PC somata and decorated PC dendrites across the molecular layer in the adult (P21) control cerebellum (Figure 2I)
After thorough examination of several adult mice (n = 9), small, infrequent granule cell (GC) heterotopia were identified in the molecular layer of each cerebellum (Figure 2C, F), just internal to an intact glia limitans (Figure 2N)
Summary
Cobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD In these severe forms of dystroglycanopathy, the muscular dystrophy and other tissue pathology is caused by mutations in genes involved in O-linked glycosylation of alpha-dystroglycan. Cerebellar histogenesis involves the formation and migration of several distinct populations of neural cells over an extended period of time, from late embryogenesis well into post-natal development [1]. This intricate and protracted developmental process renders the cerebellum susceptible to a number of insults leading to a variety of cerebellar disorders. There are distinct functions for glial and neuronal DG in the cerebrum—glial DG is critical for laminar development of the forebrain, while neuronal DG is necessary for proper hippocampal longterm potentiation [7]
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