Long distance cell migration occurs throughout the developing CNS, but the underlying cellular and molecular mechanisms are poorly understood. We show that the directed circumferential migration of basilar pontine neurons from their origin in the neuroepithelium of the dorsal hindbrain to the ventral midline involves the extension of long (>1 mm) leading processes, which marker analyses suggest are molecularly distinct from axons. In vivo analysis of knockout mice implicates the axonal chemoattractant netrin-1, functioning via its receptor Deleted in Colorectal Cancer (DCC), in attracting the leading process to the ventral midline. Direct evidence for this chemoattractant mechanism is provided, using explant cultures and time-lapse analysis in vitro. Our results demonstrate the attraction of migrating neurons in the mammalian brain by an axon guidance molecule and the chemotactic responsiveness of their leading processes.

Hypofunction of the N-methyl D-aspartate subtype of glutamate receptor (NMDAR) is hypothesized to be a mechanism underlying cognitive dysfunction in individuals with schizophrenia. For the schizophrenia-linked genes NRG1 and ERBB4, NMDAR hypofunction is thus considered a key detrimental consequence of the excessive NRG1-ErbB4 signaling found in people with schizophrenia. However, we show here that neuregulin 1β-ErbB4 (NRG1β-ErbB4) signaling does not cause general hypofunction of NMDARs. Rather, we find that, in the hippocampus and prefrontal cortex, NRG1β-ErbB4 signaling suppresses the enhancement of synaptic NMDAR currents by the nonreceptor tyrosine kinase Src. NRG1β-ErbB4 signaling prevented induction of long-term potentiation at hippocampal Schaffer collateral-CA1 synapses and suppressed Src-dependent enhancement of NMDAR responses during theta-burst stimulation. Moreover, NRG1β-ErbB4 signaling prevented theta burst-induced phosphorylation of GluN2B by inhibiting Src kinase activity. We propose that NRG1-ErbB4 signaling participates in cognitive dysfunction in schizophrenia by aberrantly suppressing Src-mediated enhancement of synaptic NMDAR function.Correspondence should be addressed to M.W.S. (mike.salter@utoronto.ca). 5 These authors contributed equally to this work.Note: Supplementary information is available on the Nature Medicine website. AUTHOR CONTRIBUTIONSG.M.P. designed the project, conducted the hippocampal experiments, analyzed the data and wrote the manuscript. L.V.K. and D.N. carried out and analyzed biochemical experiments. E.K.L. oversaw and analyzed the prefrontal cortex experiments. N.M.G. carried out and analyzed the prefrontal cortex experiments. K.T.Y. maintained, housed and provided ErbB4 knockout mice. All authors participated in revising the manuscript and agreed to the final version. M.W.S. conceived the study, analyzed data, supervised the overall project and wrote the manuscript. COMPETING FINANCIAL INTERESTSThe authors declare no competing financial interests.Reprints and permissions information is available online at http://npg.nature.com/reprintsandpermissions/. Nat Med. Author manuscript; available in PMC 2012 January 23. CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptThe NMDAR, a major excitatory ligand-gated ion channel in the central nervous system and a principal mediator of synaptic plasticity, is a multiprotein complex whose core is a heterotetramer comprising two obligate GluN1 subunits and two GluN2(A-D) subunits 1,2 . Proteins associated with the core NMDAR have key roles in trafficking, stability, subunit composition and function of NMDARs 3 . A key process regulating NMDAR activity is phosphorylation by NMDAR-associated kinases. Certain NMDAR-dependent functions, such as ventilation and locomotion, may be independent of NMDAR phosphorylation 4 , whereas phosphorylation-induced upregulation of NMDARs is critical for synaptic plasticity [5][6][7] .A prominent hypothesis for the pathophysiology of schizophrenia is that core symptoms such as...

We have recently described an IFN regulatory factor 3-mediated antiviral gene program that is induced by both Toll-like receptor (TLR)3 and TLR4 ligands. In our current study, we show that activation of IFN/viral response gene expression in primary macrophage cells is stronger and prolonged with TLR3 stimulation compared with that of TLR4. Our data also reveal that the cytoplasmic tails of both TLR3 and TLR4 can directly interact with myeloid differentiation factor 88 (MyD88). However, although Toll/IL-1 receptor homology domain-containing adaptor protein/MyD88 adaptor-like is able to associate with TLR4, we were unable to detect any interaction between Toll/IL-1 receptor homology domain-containing adaptor protein/MyD88 adaptor-like and TLR3. By using quantitative real-time PCR assays, we found that TLR3 expression is inducible by both TLR3 and TLR4 ligands, while TLR4 expression is not inducible by these same stimuli. Furthermore, using cells derived from mice deficient in the IFN-αβR, we show that both TLR3 and TLR4 require IFN-β autocrine/paracrine feedback to induce TLR3 expression and activate/enhance genes required for antiviral activity. More specifically, a subset of antiviral genes is initially induced independent of IFN-β, yet the cytokine further enhances expression at later time points. This was in contrast to a second set of genes (including TLR3) that is induced only after IFN-β production. Taken together, our data argue that, despite both TLR3 and TLR4 being able to use IFN-β to activate/enhance antiviral gene expression, TLR3 uses multiple mechanisms to enhance and sustain the antiviral response more strongly than TLR4.

Cortical development is dependent on the timely production and migration of neurons from neurogenic sites to their mature positions. Mutations in several receptors for extracellular matrix (ECM) molecules and their downstream signaling cascades produce dysplasia in brain. Although mutation of a critical binding site in the gene that encodes the ECM molecule laminin γ1 (Lamc1) disrupts cortical lamination, the ECM ligand(s) for many ECM receptors have not been demonstrated directly in the cortex. Several isoforms of the heterotrimeric laminins, all containing the β2 and γ3 chain, have been isolated from the brain, suggesting they are important for CNS function. Here, we report that mice homozygous null for the laminin β2 and γ3 chains exhibit cortical laminar disorganization. Mice lacking both of these laminin chains exhibit hallmarks of human cobblestone lissencephaly (type II, nonclassical): they demonstrate severe laminar disruption; midline fusion; perturbation of Cajal-Retzius cell distribution; altered radial glial cell morphology; and ectopic germinal zones. Surprisingly, heterozygous mice also exhibit laminar disruption of cortical neurons, albeit with lesser severity. In compound null mice, the pial basement membrane is fractured, and the distribution of a key laminin receptor, dystroglycan, is altered. These data suggest that β2 and γ3-containing laminins play an important dose-dependent role in development of the cortical pial basement membrane, which serves as an attachment site for Cajal-Retzius and radial glial cells, thereby guiding neural development.