The axon growth associated protein 43 is the most important single protein known to date in the promotion of axon growth and regeneration. Nevertheless, its gene regulation is still obscure. No transcription factors are known to control GAP-43 gene expr...

The mammalian central nervous system is largely incapable of repair, so injury to central tracts yields profoundly devastating permanent deficits. Previous studies have demonstrated that the environment surrounding the lesioned region plays a pivotal ro...

Modifications of the temporal patterns of activity along the axon may play an important role in shaping the neural code, particularly in axons that have a rich complement of voltage-gated ion channels and receptors to neuromodulators. We are studying th...

Developing axons exhibit extremely dynamic behaviors including extension, pauses and retraction. Axon retraction is a typical negative response of axons to the environment or guidance molecules, critical for axon pathfinding and small scale pruning of a...

Why do CNS neurons fail to regenerate following injury? Previous research has implicated the inhibitory properties of CNS myelin, among other factors, as a cause of CNS regenerative failure. Immunization with myelin, for example, has been shown to promo...

Disrupted-in-Schizophrenia-1 ( DISC1 ) is a candidate gene for susceptibility of schizophrenia. In the accompanying paper ([Taya et al., 2006][1]), we report that DISC1 acts as a linker between Kinesin-1 and DISC1-interacting molecules, such as NudE-like, lissencephaly-1, and 14-3-3ε. Here we identified growth factor receptor bound protein 2 (Grb2) as a novel DISC1-interacting molecule. Grb2 acts as an adaptor molecule that links receptor tyrosine kinases and the Ras–extracellular signal-regulated kinase (ERK) pathway. DISC1 formed a ternary complex with Grb2 and kinesin heavy chain KIF5A of Kinesin-1. In cultured rat hippocampal neurons, both DISC1 and Grb2 partially colocalized at the distal part of axons. Knockdown of DISC1 or kinesin light chains of Kinesin-1 by RNA interference inhibited the accumulation of Grb2 from the distal part of axons. Knockdown of DISC1 also inhibited the neurotrophin-3 (NT-3)-induced phosphorylation of ERK-1/2 at the distal part of axons and inhibited NT-3-induced axon elonga...

The mouse retina encodes diverse visual features in the spike trains of >40 retinal ganglion cell (RGC) types. Each RGC type innervates a specific subset of the >50 retinorecipient brain areas. Our catalog of RGC types and feature representations is nearing completion. Yet, we know little about where specific RGC types send their information. Furthermore, the developmental strategies by which RGC axons choose their targets and pattern their terminal arbors remain obscure. Here, we identify a genetic intersection ( Cck-Cre and Brn3cCKOAP ) that selectively labels transient Suppressed-by-Contrast (tSbC) RGCs, a member of an evolutionarily conserved functionally mysterious RGC subclass. We find that tSbC RGCs selectively innervate the dorsolateral geniculate nucleus (dLGN) and ventrolateral geniculate nucleus (vLGN) of the thalamus, the superior colliculus (SC), and the nucleus of the optic tract (NOT) in mice of either sex. They binocularly innervate dLGN and vLGN but project only contralaterally to SC and N...

Molecular mechanisms generating reciprocal organization of corticothalamic (CT) and thalamocortical (TC) projections are poorly understood. The prevailing model suggests that CT and TC projections physically interact within the subcortical telencephalon (ST) and actively guide each other to their appropriate reciprocal targets during development. Complementary gradients of EphA and ephrin-A expression, located both between as well as within specific cortical areas and their corresponding thalamic nuclei suggested their role in the formation of topographic reciprocity of TC and CT projections. Using in utero electroporation-mediated overexpression or suppression by siRNA, we found that the expression levels of EphA7 on neocortical axons control the within-nucleus topography of CT projections. This process was independent of the relative positioning of CT axons within the ST. Notably, topographic targeting of TC axons was normal in the electroporated brains in which the topography of CT axons was disrupted. ...

Rescuing neurons from death and promoting axon regeneration through the delivery of individual neurotrophic factors (NTF) to the injured CNS has proved disappointing. Combined FGF2, NT-3, and BDNF trophically supports significantly more retinal ganglion cell (RGC) survival and neurite outgrowth in the presence of inhibitory CNS myelin than does the sum of the effects of each NTF given alone. We observed similar trophic synergism of combinatorial NTF treatment in vivo after optic nerve (ON) transection and intravitreal implantation of fibroblasts transfected to express fgf2/nt-3/bdnf, which promoted enhanced RGC survival and axon regeneration and abolished scarring in the ON rich in myelin- and non-myelin-derived inhibitory ligands. Triple but not single, NTF treatment activated regulated intramembraneous proteolysis (RIP) of p75NTR, leading to a reduction in intact p75NTR, and correlated with a 30% decrease in the production of Rho-GTP, a key downstream signalling molecule in the axon growth inhibitory cas...

Midbrain dopaminergic neurons differentiate adjacent to the ventral floor plate at approximately E10.5 in the mouse. These neurons extend axons rostrally - away from the isthmus and towards the striatum (E11.5 - E14.5). To date there is limited data regarding the cues that may govern this projection. The dorsal portion of the neuroepithelium has been proposed as a source of guidance cues (Nakamura et al, 2000), and recently Slit2 and netrin-1 have been shown respectively to inhibit or promote midbrain dopaminergic axonal extension in vitro at E14.5 (Lin et al, 2005). However an analysis of the midbrain expression of axon guidance cues over the time period of axonal extension by this population remains lacking. We have addressed this using in situ hybridization techniques to probe for known axon guidance cues. In parallel studies we are addressing whether such cues have functional effects on midbrain dopaminergic neurons using an in vitro collagen co-culture assay where midbrain explants from E11.5 mice are...