The dystrophin glycoprotein complex (DGC) is a multimeric protein assembly associated with either the X-linked cytoskeletal protein dystrophin or its autosomal homologue utrophin. In striated muscle cells, the DGC links the extracellular matrix to the actin cytoskeleton and mediates three major functions: structural stability of the plasma membrane, ion homeostasis, and transmembrane signaling. Mutations affecting the DGC underlie major forms of congenital muscle dystrophies. The DGC is prominent also in the central and peripheral nervous system and in tissues with a secretory function or which form barriers between functional compartments, such as the blood-brain barrier, choroid plexus, or kidney. A considerable molecular heterogeneity arises from cell-specific expression of its constituent proteins, notably short C-terminal isoforms of dystrophin. Experimentally, the generation of mice carrying targeted gene deletions affecting the DGC has clarified the interdependence of DGC proteins for assembly of the complex and revealed its importance for brain development and regulation of the 'milieu intérieur. Here, we focus on recent studies of the DGC in brain, blood-brain barrier and choroid plexus, retina, and kidney and discuss the role of dystrophin isoforms and utrophin for assembly of the complex in these tissues.
Multiple GABAA-receptor subtypes are assembled from alpha, beta and gamma subunit variants. GABAA receptors containing the alpha3 subunit represent a minor population with a restricted distribution in the CNS. In addition, they predominate in monoaminergic neurons and in the nucleus reticularis thalami (nRT), suggesting a role in the regulation of cortical function and sleep. Mice with a targeted deletion of the alpha3 subunit gene (alpha3(0/0)) are viable and exhibit a subtle behavioural phenotype possibly related to dopaminergic hyperfunction. Here, we investigated immunohistochemically the consequences of the loss of alpha3 subunit for maturation of GABAA receptors and formation of GABAergic synapses in the nRT. Throughout postnatal development, the regional distribution of the alpha1, alpha2, or alpha5 subunit was unaltered in alpha3(0/0) mice and the prominent alpha3 subunit staining of nRT neurons in wildtype mice was not replaced. Subcellularly, as seen by double immunofluorescence, the alpha3 and gamma2 subunit were clustered at postsynaptic sites in the nRT of adult wildtype mice along with the scaffolding protein gephyrin. In alpha3(0/0) mice, gamma2 subunit clustering was disrupted and gephyrin formed large aggregates localized at the cell surface, but unrelated to postsynaptic sites, indicating that nRT neurons lack postsynaptic GABAA receptors in mutant mice. Furthermore, GABAergic terminals were enlarged and reduced in number, suggesting a partial deficit of GABAergic synapses. Therefore, GABAA receptors are required for gephyrin clustering and long-term synapse maintenance. The absence of GABAA-mediated transmission in the nRT may have a significant impact on the function of the thalamo-cortical loop of alpha3(0/0) mice.
The dystrophin-associated protein complex (DPC) consisting of syntrophin, dystrobrevin, and dystroglycan isoforms is associated either with dystrophin or its homolog utrophin. It is present not only in muscle cells, but also in numerous tissues, including kidney, liver, and brain. Using high-resolution immunofluorescence imaging and Western blotting, we have investigated the effects of utrophin and dystrophin gene deletion on the formation and membrane anchoring of the DPC in kidney epithelial cells, which co-express utrophin and low levels of the C-terminal dystrophin isoform Dp71. We show that multiple, molecularly distinct DPCs co-exist in the nephron; these DPCs have a segment-specific distribution and are only partially associated with utrophin in the basal membrane of tubular epithelial cells. In utrophin-deficient mice, a selective reduction of beta2-syntrophin has been observed in medullary tubular segments, whereas alpha1-syntrophin and beta1-syntrophin are retained, concomintant with an upregulation of beta-dystroglycan, beta-dystrobrevin, and Dp71. These findings suggest that beta2-syntrophin is dependent on utrophin for association with the DPC, and that loss of utrophin is partially compensated by Dp71, allowing the preservation of the DPC in kidney epithelial cells. This hypothesis is confirmed by the almost complete loss of all DPC proteins examined in mice lacking full-length utrophin and all C-terminal dystrophin isoforms (utrophin(0/0)/mdx(3Cv)). The DPC thus critically depends on these proteins for assembly and/or membrane localization in kidney epithelial cells.
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