2 mark the locations of basement membrane disruption where cell processes protrude into the subarachnoid space

2 mark the locations of basement membrane disruption where cell processes protrude into the subarachnoid space. glycosylation in distinct cell types of the CNS may contribute to the diversity of dystroglycan function in the CNS, as well as to the broad clinical spectrum of type II lissencephalies. Introduction The Lep laminar development of the cerebral cortex is dependent on the proliferation of neuronal precursors, scaffolding of radial glia, interactions between glia and neurons, and the presence of external localization cues (Diaz and Gleeson, 2009). Genetic mutations that impair these processes are associated ML224 with cognitive impairment and epilepsy, as well as structural malformations (Guerrini and Carrozzo, 2001; Ross and Walsh, 2001; Mochida and Walsh, 2004; Guerrini et al., 2008). A subset of congenital muscular dystrophies (CMDs), including Fukuyama-type congenital muscular dystrophy (FCMD), muscle-eye-brain disease (MEB), and WalkerCWarburg syndrome (WWS), feature brain defects that include cobblestone (type II) lissencephaly (Muntoni and Voit, 2004). In contrast to type I (classical) lissencephaly, which is characterized by a four-layer cerebral cortex, cobblestone lissencephaly is characterized by glial/neuronal heterotopia that disrupt the laminar organization of the cerebral cortex (Olson and Walsh, 2002). The genes linked to CMD-associated cobblestone lissencephaly encode known or putative glycosyltransferases, and muscle biopsies show that -dystroglycan is hypoglycosylated ML224 in patients (Kobayashi et al., 1998; Yoshida et al., 2001; Beltrn-Valero de Bernab et al., 2002, 2004; Barresi et al., 2004; van Reeuwijk et al., 2005, 2007; Godfrey et al., 2007; Clement et al., 2008). Dystroglycan is composed of and subunits that are noncovalently associated (Ibraghimov-Beskrovnaya et al., 1992, 1993). The subunit of dystroglycan (-dystroglycan) is an extracellular protein that binds laminin and laminin G-like domains of perlecan, agrin, neurexin, and pikachurin (Smalheiser and Schwartz, 1987; Bowe et al., 1994; Gee et al., 1994; Talts et al., 1999; Sugita et al., 2001; Sato et al., 2008). The subunit of dystroglycan (-dystroglycan) contains a single transmembrane domain, and its cytoplasmic tail binds dystrophin (Ervasti and Campbell, 1993). Dystroglycan forms a transmembrane link between the extracellular matrix and the intracellular actin cytoskeleton through its interactions with laminin and dystrophin. In skeletal muscle, this link provides structural integrity to the sarcolemma (Ervasti and Campbell, 1993). In addition, the cytoplasmic domain of -dystroglycan is associated with rapsyn and the Ras/MAPK signaling pathway through the adapter protein Grb2 (Yang et al., 1995; Oak et al., 2003; Moore and Winder, 2010). Previous immunohistochemical and hybridization studies indicate that dystroglycan is expressed in migrating neurons as well as in radially oriented glia during CNS development (Henion et al., 2003; Ohtsuka-Tsurumi et al., 2004). It is not known ML224 whether dystroglycan mediates neuron-glia interactions or response to external cues during neuron migration. Dystroglycan binds – and -neurexins (Sugita et al., 2001), and these interactions might mediate neuron-glia adhesions. Furthermore, dystroglycan is a receptor for laminin, perlecan, and agrinCextracellular matrix proteins that are important to the organization and development of both the PNS and CNS (Smalheiser and Schwartz, 1987; Bowe et al., 1994; Miner et al., 1998; Ruegg and Bixby, 1998; Costell et al., 1999; Talts et al., 1999; Occhi et al., 2005; Chen et al., 2009). Here we provide genetic evidence that dystroglycan has distinct functions in glia and neurons of the adult and developing CNS. Dystroglycan stabilizes the glial limitans basement membrane during cerebral cortex development and, in contrast to its mode of operation in skeletal muscle, this function is independent of the -dystroglycan cytoplasmic domain. Neuronal expression of – and -dystroglycan was dispensible for the laminar development of the cerebral cortex; however, deletion of dystroglycan in neurons blunted hippocampal long-term potentiation (LTP), indicating a novel role in synaptic plasticity. Materials and Methods Generation of dystroglycan-deficient mice. The generation of the floxed-dystroglycan mouse strain was previously described (Cohn et al., 2002). Heterozygous floxed dystroglycan (Dag1lox/lox) mice were bred to hemizygous mice expressing promoter drives expression of Cre recombinase in glia and neurons throughout the CNS, beginning by embryonic day 10.5 (Tronche et al., 1999; Graus-Porta et al., 2001). = 24) (Fig. 2), indicating that hydrocephalus was present before the fusion of the cranial sutures in some mice. Gross examination.