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The Journal of Neuroscience, August 20, 2008, 28(34)
This Week in The Journal
This Week in The Journal
Cellular/Molecular
Wnt Effects on Growth Cone Microtubules
Silvia A. Purro, Lorenza Ciani, Monica Hoyos-Flight, Eleanna Stamatakou, Eliza Siomou, and Patricia C. Salinas
(see pages 8644–8654)
Wnt family proteins are secreted from target tissues and regulate axonal terminal arborization during development. In the canonical Wnt pathway, Wnt signals through the phosphoprotein Dishevelled, which leads to inhibition of the kinase Gsk3, elevation of β-catenin, and activation of transcription. Purro et al. now describe an unexpected transcription-independent action of Wnt signaling. Wnt3a rapidly slowed axonal growth from cultured mouse dorsal root ganglion neurons, while growth cones grew larger. Rather than splaying out toward the leading edge, microtubules grew transversely in these enlarged growth cones, forming kinks and loops reminiscent of changes that occur during terminal arborization. This effect appeared to be mediated by dissociation of the tumor-suppressor protein adenomatous polyposis coli (APC) from the plus-ends of microtubules specifically in growth cones, and it required proper functioning of Dishevelled and Gsk3. Knockdown of APC via RNA inhibition mimicked the effects of Wnt3, producing looped microtubules and increasing growth cone size.
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In control DRG growth cones (top), APC (red) is present at the plus-ends of splayed microtubules (green). Wnt3a treatment (bottom) causes growth cone enlargement, microtubule bending and looping, and decreased APC at microtubule plus-ends. See the article by Purro et al. for details.
Development/Plasticity/Repair
Hair-Cell Innervation in Zebrafish
Aaron Nagiel, Daniel Andor-Ardó, and A. J. Hudspeth
(see pages 8442–8453)
To study synaptogenesis, it is desirable to observe single axons growing and contacting targets in vivo, and then confirm synapse formation using electron microscopy (EM). This has been problematic, however, because the available techniques require coexpression of two labels or can be toxic. Nagiel et al. therefore developed HRP-mCherry, a transmembrane fusion protein with an intracellular fluorescent moiety for in vivo visualization and an extracellular horseradish peroxidase that allows visualization by EM. Because the two domains form a single protein, the labeling seen with EM is proportional to that seen fluorescently. Using this technique, the authors examined innervation of hair cells in the lateral line of zebrafish. They show that single afferents innervated multiple hair cells, all of which had the same polarity (i.e., they sense the same direction of water currents). After hair-cell ablation and regeneration, afferents reinnervated hair cells of the same polarity that they originally innervated.
Behavioral/Systems/Cognitive
Whole-Cell Recordings of Binocular Inputs to V1
Nicholas J. Priebe
(see pages 8553–8559)
Ocular dominance, which measures the relative strength of input that a cortical neuron receives from each eye, has been studied extensively with extracellular electrodes and other spike-rate-dependent measures. Spike rate might not accurately reflect synaptic inputs from each eye, however, because such inputs might not drive the membrane potential to spiking threshold. Priebe demonstrates this by modeling the nonlinear transformation between membrane fluctuations and spiking. He shows that small changes in membrane potential can result in large differences in spiking and thus in increased apparent ocular dominance. Using in vivo whole-cell patch recordings in cat visual cortex, he then demonstrates that more neurons receive synaptic inputs from both eyes (as measured by membrane potential fluctuations) than is suggested by spike rate. In this sense, neurons are less monocular than previously reported. This has relevance for studies of developmental plasticity in which monocular deprivation has been reported to alter ocular dominance.
Neurobiology of Disease
Estradiol-Mediated Neuroprotection
Quan-Guang Zhang, Ruimin Wang, Mohammad Khan, Virendra Mahesh, and Darrell W. Brann
(see pages 8430–8441)
Estradiol is protective against stroke and neurodegeneration associated with Alzheimer's disease (AD) and other neurodegenerative diseases. This week, Zhang et al. identify molecular mechanisms mediating estradiol's neuroprotective effects in rat hippocampal CA1 neurons after cerebral ischemia. In addition to preventing ischemia-induced neuronal death, estradiol increased the expression of Wnt3, activating the Wnt-β-catenin pathway. Nuclear levels of the transcription factor β-catenin were also increased, as was expression of the antiapoptotic protein survivin, a target of β-catenin. Estradiol also prevented ischemia-induced upregulation of an inhibitor of Wnt signaling, dickkopf-1 (Dkk1), by preventing activation of c-Jun N-terminal kinase (JNK) and its substrate, the transcription factor c-Jun. A JNK inhibitor mimicked the protective effects of estradiol, whereas exogenous Dkk1 prevented these effects. Dkk1 has been linked to tau hyperphosphorylation in AD, and Zhang et al. show that ischemia also increased phosphorylation of tau, and estradiol and JNK inhibitors blocked this effect.
Related articles in J. Neurosci.:
- Role of Dickkopf-1, an Antagonist of the Wnt/β-Catenin Signaling Pathway, in Estrogen-Induced Neuroprotection and Attenuation of Tau Phosphorylation
- Quan-Guang Zhang, Ruimin Wang, Mohammad Khan, Virendra Mahesh, and Darrell W. Brann
J. Neurosci. 2008 28: 8430-8441.[Abstract] [Full Text] - Specificity of Afferent Synapses onto Plane-Polarized Hair Cells in the Posterior Lateral Line of the Zebrafish
- Aaron Nagiel, Daniel Andor-Ardó, and A. J. Hudspeth
J. Neurosci. 2008 28: 8442-8453.[Abstract] [Full Text] - The Relationship between Subthreshold and Suprathreshold Ocular Dominance in Cat Primary Visual Cortex
- Nicholas J. Priebe
J. Neurosci. 2008 28: 8553-8559.[Abstract] [Full Text] - Wnt Regulates Axon Behavior through Changes in Microtubule Growth Directionality: A New Role for Adenomatous Polyposis Coli
- Silvia A. Purro, Lorenza Ciani, Monica Hoyos-Flight, Eleanna Stamatakou, Eliza Siomou, and Patricia C. Salinas
J. Neurosci. 2008 28: 8644-8654.[Abstract] [Full Text]
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