Cellular/Molecular
Many mRNAs Are Present in Axonal Growth Cones
Krishna H. Zivraj, Yi Chun Loraine Tung, Michael Piper, Laura Gumy, James W. Fawcett, et al.
(see pages 15464–15478)
The soma was long thought to be the sole site of protein synthesis in neurons. The discovery of polyribosomes near dendritic spines and the subsequent detection of protein synthesis in axonal growth cones led to the hypothesis that local translation of some growth-associated proteins underlies rapid changes during growth, synaptogenesis, and plasticity. This hypothesis has gained support from screens of candidate molecules, which detected mRNAs encoding cytoskeleton-related proteins in growth cones. Using unbiased, genome-wide profiling, Zivraj et al. found that an unexpectedly large, diverse set of transcripts (1000–2000) was present in growth cones of developing retinal ganglion cell axons in Xenopus and mice. In Xenopus, the mRNA composition of growth cones only partially overlapped with that of axonal shafts, and the composition changed as axons matured. Transcripts encoding guidance molecules and their receptors were present, as were mRNAs encoding presynaptic proteins. But the most abundant mRNAs were those involved in protein translation and its regulation.
Development/Plasticity/Repair
PTEN Activation by ProNGF Inhibits Effects of BDNF
Wenyu Song, Marta Volosin, Andrea B. Cragnolini, Barbara L. Hempstead, and Wilma J. Friedman
(see pages 15608–15615)
Mature forms of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) derive from larger precursor proteins, proNGF and proBDNF. Proneurotrophins can be processed in the endoplasmic reticulum and Golgi apparatus or secreted and cleaved extracellularly. Mature neurotrophins bind to Trk receptors, which activate phosphoinositide 3-kinase (PI3K), which in turn activates the kinase Akt, ultimately promoting differentiation, synaptogenesis, and survival. In contrast, unprocessed, secreted proneurotrophins bind to p75NTR–sortillin receptor complexes and induce apoptosis. When simultaneously presented to cultured rat basal forebrain neurons, the apoptotic effects of proNGF eliminate the prosurvival effects of BDNF by preventing activation of Akt. Song et al. now show that proNGF increases levels of PTEN, a phosphatase that inactivates PI3K, in basal forebrain neurons. When PTEN was inhibited, the prosurvival effects of BDNF overrode the apoptotic effects of proNGF. Moreover, PTEN inhibitors reduced proNGF-associated death of hippocampal neurons following seizure in vivo, suggesting potential therapeutic value.
Behavioral/Systems/Cognitive
Different Mechanisms Produce Orientation Selectivity in RGCs
Sowmya Venkataramani and W. Rowland Taylor
(see pages 15664–15676)
Some retinal ganglion cells (RGCs) respond preferentially to bars of a particular orientation. Only two classes of orientation-selective RGCs exist, however: horizontally selective and vertically selective. It has been argued that orientation selectivity in visual cortical neurons can be based solely from excitatory inputs from linearly arranged thalamic neurons, without inhibitory feedback. Orientation selectivity in RGCs, in contrast, requires inhibitory GABAergic inputs. To better understand how orientation selectivity arises in RGCs, Venkataramani and Taylor examined its synaptic basis in rabbit. The response patterns of vertically selective and horizontally selective RGCs were similar: preferred stimuli activated glutamatergic receptors in both cell types, and GABAergic and glycinergic inhibition contributed to orientation selectivity in both cases. Surprisingly, however, the synaptic connectivity mediating orientation selectivity differed. Most notably, during nonpreferred stimulation, GABA directly inhibited horizontally selective RGCs, whereas it inhibited glutamatergic inputs to vertically selective cells. Furthermore, glycinergic disinhibition contributed to excitation during preferred stimulation only for vertically selective RGCs.
Orientation selectivity is generated by different presynaptic mechanisms in vertically selective (left) and horizontally selective (right) RGCs. See the article by Venkataramani and Taylor for details.
Neurobiology of Disease
NEEP21 Influences Processing of APP
Eric M. Norstrom, Can Zhang, Rudolph Tanzi, and Sangram S. Sisodia
(see pages 15677–15685)
The transmembrane protein amyloid precursor protein (APP) is cleaved by α- or β-secretase and then by γ-secretase to generate intracellular and extracellular fragments. When β-secretase cleaves APP, the second cleavage produces β-amyloid, which oligomerizes and forms plaques characteristic of Alzheimer's disease (AD). Although production of β-amyloid has been linked to cognitive deficits in AD, impaired functioning of APP, α-, β-, and γ-secretases, and/or other APP cleavage products might also contribute to the pathology. Identifying the functions of APP could be aided by identifying proteins it interacts with in vivo, as Norstrom et al. have done in mice. One interacting protein was neuron-enriched endosomal protein of 21 kDa (NEEP21), a protein involved in recycling and trafficking of endocytosed membrane proteins, including glutamate receptors. Decreasing NEEP21 levels in neuroblastoma cells that expressed an AD-associated form of APP decreased APP cleavage by α-secretase, whereas increasing NEEP21 decreased cleavage by β-secretase, indicating that NEEP21 influences amyloidogenic processing of APP.
