The phenotypic similarities between the B3gnt1 and ISPD mutants raised the intriguing possibility that they function in the same genetic pathway to regulate axon guidance. B3gnt1 has been implicated as a dystroglycan glycosyltransferase in tumor cell

lines in vitro ( Bao et al., 2009), and mutations in ISPD were recently identified in patients with Walker-Warburg syndrome, http://www.selleckchem.com/PI3K.html a neurodevelopmental disorder characterized by defective glycosylation of dystroglycan ( Roscioli et al., 2012; Willer et al., 2012). While dystroglycan is known to be required for neuronal migration in the brain, it has not previously been implicated in regulating axon guidance. To determine if the axon guidance defects observed in B3gnt1 and ISPD mutants are due to defects in dystroglycan function, we generated mice in which dystroglycan was deleted from the epiblast (Sox2cre; DGF/−) to circumvent the early embryonic lethality associated with germline deletion of dystroglycan. Indeed, Sox2cre; DGF/− mice exhibit the same axon

guidance defects as B3gnt1 and ISPD mutants, with abnormal formation of the descending hindbrain axonal tract and severe defasciculation of the spinal cord dorsal funiculus ( Figures 1B and 1E). These findings thus reveal a requirement for dystroglycan in regulating axon guidance. Dystroglycan functions in vivo in the assembly and maintenance of basement membranes by acting as a receptor and scaffold for several ECM proteins (Barresi and Campbell, 2006). Dystroglycan undergoes extensive glycosylation in vivo, and ligand binding to dystroglycan is

strictly dependent on its proper glycosylation. Importantly, Vemurafenib clinical trial human patients with mutations in dystroglycan or its glycosyltransferases develop a spectrum of congenital also muscular dystrophies that are often accompanied by a range of neurological defects. These disorders are collectively referred to as dystroglycanopathies, and their pathological hallmarks are recapitulated in mouse models with deletions in orthologous genes (Hewitt, 2009; Moore et al., 2002; Satz et al., 2008). Interestingly, several studies indicate that the majority of human patients with pathological defects in dystroglycan glycosylation have mutations of unknown etiology, suggesting that additional unknown glycosyltransferases are required for dystroglycan function in vivo (Mercuri et al., 2009). While B3gnt1M155T/M155T mice are born at normal Mendelian ratios and display a mild muscular dystrophy phenotype of variable penetrance, B3gnt1LacZ/LacZ embryos failed to survive beyond E9.5, indicating that B3gnt1 is required for normal embryonic development and that the M155T mutation generates a hypomorphic allele. B3gnt1LacZ/LacZ early embryonic lethality is consistent with a role for B3gnt1 in regulating dystroglycan glycosylation and function in vivo, since mice deficient for dystroglycan die around E7.