This is an RSS newsfeed from BioMed Central It is intended to be used with an RSS reader. For more information about RSS newsfeeds from BioMed Central, visit http://www.biomedcentral.com/info/about/rss/ http://www.neuraldevelopment.com The latest articles from Neural Development (ISSN 1749-8104) published by BioMed Central Background: β-Amyloid precursor protein (APP) has been reported to play a role in the outgrowth of neurites from cultured neurons. Both cell-surface APP and its soluble, ectodomain cleavage product (APPs-α) have been implicated in regulating the length and branching of neurites in a variety of assays, but the mechanism by which APP performs this function is not understood. Results: Here, we report that APP is required for proper neurite outgrowth in a cell autonomous manner, both in vitro and in vivo. Neurons that lack APP undergo elongation of their longest neurite. Deletion of APLP1 or APLP2, homologues of APP, likewise stimulates neurite lengthening. Intriguingly, wild-type neurons exposed to APPs-α, the principal cleavage product of APP, also undergo neurite elongation. However, APPs-α is unable to stimulate neurite elongation in the absence of cellular APP expression. The outgrowth-enhancing effects of both APPs-α and the deletion of APP are inhibited by blocking antibodies to Integrin β1 (Itgβ1). Moreover, full length APP interacts biochemically with Itgβ1, and APPs-α can interfere with this binding. Conclusion: Our findings indicate that APPs-α regulates the function of APP in neurite outgrowth via the novel mechanism of competing with the binding of APP to Itgβ1. http://www.neuraldevelopment.com/content/3/1/15 Tracy L Young-Pearse, Allen C Chen, Rui Chang, Cesar Marquez and Dennis J Selkoe Neural Development 2008, 3:15 2008-06-23 doi:10.1186/1749-8104-3-15 Neural Development 1749-8104 3 15 2008-06-23 Background: Branchiomotor neurons comprise an important class of cranial motor neurons that innervate the branchial-arch-derived muscles of the face, jaw and neck. They arise in the ventralmost progenitor domain of the rhombencephalon characterized by expression of the homeodomain transcription factors Nkx2.2 and Phox2b. Phox2b in particular plays a key role in the specification of branchiomotor neurons. In its absence, generic neuronal differentiation is defective in the progenitor domain and no branchiomotor neurons are produced. Conversely, ectopic expression of Phox2b in spinal regions of the neural tube promotes cell cycle exit and neuronal differentiation and, at the same time, induces genes and an axonal phenotype characteristic for branchiomotor neurons. How Phox2b exerts its pleiotropic functions, both as a proneural gene and a neuronal subtype determinant, has remained unknown. Results: To gain further insights into the genetic program downstream of Phox2b, we searched for novel Phox2b-regulated genes by cDNA microarray analysis of facial branchiomotor neuron precursors from heterozygous and homozygous Phox2b mutant embryos. We selected for functional studies the genes encoding the axonal growth promoter Gap43, the Wnt antagonist Sfrp1 and the transcriptional regulator Sox13, which were not previously suspected to play roles downstream of Phox2b and whose expression was affected by Phox2b misexpression in the spinal cord. While Gap43 did not produce an obvious phenotype when overexpressed in the neural tube, Sfrp1 induced the interneuron marker Lhx1,5 and Sox13 inhibited neuronal differentiation. We then tested whether Sfrp1 and Sox13, which are down-regulated by Phox2b in the facial neuron precursors, would antagonize some aspects of Phox2b activity. Co-expression of Sfrp1 prevented Phox2b from repressing Lhx1,5 and alleviated the commissural axonal phenotype. When expressed together with Sox13, Phox2b was still able to promote cell cycle exit and neuronal differentiation, but the cells failed to relocate to the mantle layer and to extinguish the neural stem cell marker Sox2. Conclusion: Our results suggest novel roles for Sfrp1 and Sox13 in neuronal subtype specification and generic neuronal differentiation, respectively, and indicate that down-regulation of Sfrp1 and Sox13 are essential aspects of the genetic program controlled by Phox2b in cranial motoneurons. http://www.neuraldevelopment.com/content/3/1/14 Patrick Pla, Marie-Rose Hirsch, Stéphane Le Crom, Simone Reiprich, Vincent R Harley and Christo Goridis Neural Development 2008, 3:14 2008-06-19 doi:10.1186/1749-8104-3-14 Neural Development 1749-8104 3 14 2008-06-19 Background: Homeodomain proteins play critical roles in shaping the development of the embryonic central nervous system in mammals. After birth, neurogenic activities are relegated to stem cell niches, which include the subgranular layer of the dentate gyrus of the hippocampus. Here, we have analyzed the function of HOP (Homeodomain only protein) in this stem cell niche and in human glioblastomas. Results: We find that HOP is strongly expressed by radial astrocytes of the dentate gyrus in mice, which are stem cells that give rise to hippocampal granular neurons throughout adulthood. Deletion or down-regulation of HOP results in a decrease of apoptosis of these stem cells without changes in proliferation, and in an increase in the number of newly formed granule neurons. We also find that human glioblastomas largely lack HOP expression and that reintroduction of HOP function in glioma cells cultured as gliomaspheres leads to enhanced apoptosis in a subset of cases. In these cells, HOP function decreases clonogenicity. Conclusion: These data suggest that HOP participates in the regulation of the adult mouse hippocampal stem cell niche by negatively affecting cell survival. In addition, HOP may work as a tumor suppressor in a subset of glioblastomas. HOP function thus appears to be critical in the adult brain in a region of continued plasticity, and its deregulation may contribute to disease. http://www.neuraldevelopment.com/content/3/1/13 Arianna De Toni, Marie Zbinden, Jonathan A Epstein, Ariel Ruiz i Altaba, Alain Prochiantz and Isabelle Caillé Neural Development 2008, 3:13 2008-05-28 doi:10.1186/1749-8104-3-13 Neural Development 1749-8104 3 13 2008-05-28 Background: In the adult abdomen of Drosophila, the shafts of mechanosensory bristles point consistently from anterior to posterior. This is an example of planar cell polarity (PCP); some genes responsible for PCP have been identified. Each adult bristle is made by a clone of four cells, including the neuron that innervates it, but little is known as to how far the formation or positions of these cells depends on PCP. The neurons include a single dendrite and an axon; it is not known whether the orientation of these processes is influenced by PCP. Results: We describe the development of the abdominal mechanosensory bristles in detail. The division of the precursor cell gives two daughters, one (pIIa) divides to give rise to the bristle shaft and socket cell and the other (pIIb) generates the neuron, the sheath and the fifth cell. Although the bristles and their associated shaft and socket cells are consistently oriented, the positioning and behaviour of the neuron, the sheath and the fifth cell, as well as the orientation of the axons and the dendritic paths, depend on location. For example, in the anterior zone of the segment, the axons grow posteriorly, while in the posterior zone, they grow anteriorly. Manipulating the PCP genes can reverse bristle orientation, change the path taken by the dendrite and the position of the cell body of the neuron. However, the paths taken by the axon are not affected. Conclusion: PCP genes, such as starry night and dachsous orient the bristles and position the neuronal cell body and affect the shape of the dendrites. However, these PCP genes do not appear to change the paths followed by the sensory axons, which must, therefore, be polarised by other factors. http://www.neuraldevelopment.com/content/3/1/12 Caroline CG Fabre, José Casal and Peter A Lawrence Neural Development 2008, 3:12 2008-04-30 doi:10.1186/1749-8104-3-12 Neural Development 1749-8104 3 12 2008-04-30 Analysis of cell-cell interactions, cell function and cell lineages greatly benefits selective destruction techniques, which, at present, rely on dedicated, high energy, pulsed lasers and are limited to cells that are detectable by conventional microscopy. We present here a high resolution/sensitivity technique based on confocal microscopy and relying on commonly used UV lasers. Coupling this technique with time-lapse enables the destruction and following of any cell(s) in any pattern(s) in living animals as well as in cell culture systems. http://www.neuraldevelopment.com/content/3/1/11 Laurent Soustelle, Benoît Aigouy, Marie-Laure Asensio and Angela Giangrande Neural Development 2008, 3:11 2008-04-28 doi:10.1186/1749-8104-3-11 Neural Development 1749-8104 3 11 2008-04-28 Background: Cell adhesion molecules have long been implicated in the regulation of axon growth, but the precise cellular roles played by individual cell adhesion molecules and the molecular basis for their action are still not well understood. We have used the sensory system of the Drosophila embryo to shed light on the mechanism by which the L1-type cell adhesion molecule Neuroglian regulates axon growth. Results: We have found a highly penetrant sensory axon stalling phenotype in neuroglian mutant embryos. Axons stalled at a variety of positions along their normal trajectory, but most commonly in the periphery some distance along the peripheral nerve. All lateral and dorsal cluster sensory neurons examined, except for the dorsal cluster neuron dbd, showed stalling. Sensory axons were never seen to project along inappropriate pathways in neuroglian mutants and stalled axons showed normal patterns of fasciculation within nerves. The growth cones of stalled axons possessed a simple morphology, similar to their appearance in wild-type embryos when advancing along nerves. Driving expression of the wild-type form of Neuroglian in sensory neurons alone rescued the neuroglian mutant phenotype of both pioneering and follower neurons. A partial rescue was achieved by expressing the Neuroglian extracellular domain. Over/mis-expression of Neuroglian in all neurons, oenocytes or trachea had no apparent effect on sensory axon growth. Conclusion: We conclude that Neuroglian is necessary to maintain axon advance along axonal substrates, but is not required for initiation of axon outgrowth, axon fasciculation or recognition of correct growth substrates. Expression of Neuroglian in sensory neurons alone is sufficient to promote axon advance and the intracellular region of the molecule is largely dispensable for this function. It is unlikely, therefore, that Nrg acts as a molecular 'clutch' to couple adhesion of F-actin within the growth cone to the extracellular substrate. Rather, we suggest that Neuroglian mediates sensory axon advance by promoting adhesion of the surface of the growth cone to its substrate. Our finding that stalling of a pioneer sensory neuron is rescued by driving Neuroglian in sensory neurons alone may suggest that Neuroglian can act in a heterophilic fashion. http://www.neuraldevelopment.com/content/3/1/10 Veronica Martin, Eli Mrkusich, Martin C Steinel, Jason Rice, David J Merritt and Paul M Whitington Neural Development 2008, 3:10 2008-04-08 doi:10.1186/1749-8104-3-10 Neural Development 1749-8104 3 10 2008-04-08 Background: Functional lateralization is a conserved feature of the central nervous system (CNS). However, underlying left-right asymmetries within neural circuitry and the mechanisms by which they develop are poorly described. Results: In this study, we use focal electroporation to examine the morphology and connectivity of individual neurons of the lateralized habenular nuclei. Habenular projection neurons on both sides of the brain share a stereotypical unipolar morphology and elaborate remarkable spiraling terminal arbors in their target interpeduncular nucleus, a morphology unlike that of any other class of neuron described to date. There are two quite distinct sub-types of axon arbor that differ both in branching morphology and in their localization within the target nucleus. Critically, both arbor morphologies are elaborated by both left and right-sided neurons, but at greatly differing frequencies. We show that these differences in cell type composition account for the gross connectional asymmetry displayed by the left and right habenulae. Analysis of the morphology and projections of individual post-synaptic neurons suggests that the target nucleus has the capacity to either integrate left and right inputs or to handle them independently, potentially relaying information from the left and right habenulae within distinct downstream pathways, thus preserving left-right coding. Furthermore, we find that signaling from the unilateral, left-sided parapineal nucleus is necessary for both left and right axons to develop arbors with appropriate morphology and targeting. However, following parapineal ablation, left and right habenular neurons continue to elaborate arbors with distinct, lateralized morphologies. Conclusion: By taking the analysis of asymmetric neural circuitry to the level of single cells, we have resolved left-right differences in circuit microarchitecture and show that lateralization can be recognized at the level of the morphology and connectivity of single projection neuron axons. Crucially, the same circuitry components are specified on both sides of the brain, but differences in the ratios of different neuronal sub-types results in a lateralized neural architecture and gross connectional asymmetry. Although signaling from the parapineal is essential for the development of normal lateralization, additional factors clearly act during development to confer left-right identity upon neurons in this highly conserved circuit. http://www.neuraldevelopment.com/content/3/1/9 Isaac H Bianco, Matthias Carl, Claire Russell, Jonathan DW Clarke and Stephen W Wilson Neural Development 2008, 3:9 2008-03-31 doi:10.1186/1749-8104-3-9 Neural Development 1749-8104 3 9 2008-03-31 Background: Neurons receive excitatory synaptic inputs that are distributed across their dendritic arbors at densities and with spatial patterns that influence their output. How specific synaptic distributions are attained during development is not well understood. The distribution of glutamatergic inputs across the dendritic arbors of mammalian retinal ganglion cells (RGCs) has long been correlated to the spatial receptive field profiles of these neurons. Thus, determining how glutamatergic inputs are patterned onto RGC dendritic arbors during development could provide insight into the cellular mechanisms that shape their functional receptive fields. Results: We transfected developing and mature mouse RGCs with plasmids encoding fluorescent proteins that label their dendrites and glutamatergic postsynaptic sites. We found that as dendritic density (dendritic length per unit area of dendritic field) decreases with maturation, the density of synapses along the dendrites increases. These changes appear coordinated such that RGCs attain the mature average density of postsynaptic sites per unit area (areal density) by the time synaptic function emerges. Furthermore, stereotypic centro-peripheral gradients in the areal density of synapses across the arbor of RGCs are established at an early developmental stage. Conclusion: The spatial pattern of glutamatergic inputs onto RGCs arises early in synaptogenesis despite ensuing reorganization of dendritic structure. We raise the possibility that these early patterns of synaptic distributions may arise from constraints placed on the number of contacts presynaptic neurons are able to make with the RGCs. http://www.neuraldevelopment.com/content/3/1/8 Josh L Morgan, Timm Schubert and Rachel OL Wong Neural Development 2008, 3:8 2008-03-26 doi:10.1186/1749-8104-3-8 Neural Development 1749-8104 3 8 2008-03-26 Background: Neural development consists of a series of steps, including neurogenesis, patterning, cell migration, axon guidance, and finally, synaptogenesis. Because all these steps proceed in a constantly changing environment, functional gene analyses during development have to take time into account. This is quite challenging, however, as loss-of-function approaches based on classic genetic tools do not allow for the precise temporal control that is required for developmental studies. Gene silencing by RNA interference (RNAi) in combination with the chicken embryo or with cultured embryos opens new possibilities for functional gene analysis in vivo. Axonin-1/TAG-1 is a cell adhesion molecule of the immunoglobulin superfamily with a well defined temporal and spatial expression pattern in the developing vertebrate nervous system. Axonin-1/TAG-1 was shown to promote neurite outgrowth in vitro and to be required for commissural and sensory axon pathfinding in vivo. Results: To knock down axonin-1 in a temporally and spatially controlled manner during development of the nervous system, we have combined RNAi with the accessibility of the chicken embryo even at late stages of development. Using ex ovo RNAi, we analyzed the function of axonin-1/TAG-1 in cerebellar development. Axonin-1 is expressed in postmitotic granule cells while they extend their processes, the parallel fibers. In the absence of axonin-1 these processes still extend but no longer in a parallel manner to each other or to the pial surface of the cerebellum. Conclusion: Axonin-1/TAG-1 is required for the navigation, but not for the elongation, of granule cell processes in the developing cerebellum in vivo. http://www.neuraldevelopment.com/content/3/1/7 Thomas Baeriswyl and Esther T Stoeckli Neural Development 2008, 3:7 2008-03-17 doi:10.1186/1749-8104-3-7 Neural Development 1749-8104 3 7 2008-03-17 Background: How axon guidance signals regulate growth cone behavior and guidance decisions in the complex in vivo environment of the central nervous system is not well understood. We have taken advantage of the unique features of the zebrafish embryo to visualize dynamic growth cone behaviors and analyze guidance mechanisms of axons emerging from a central brain nucleus in vivo. Results: We investigated axons of the nucleus of the medial longitudinal fascicle (nucMLF), which are the first axons to extend in the zebrafish midbrain. Using in vivo time-lapse imaging, we show that both positive axon-axon interactions and guidance by surrounding tissue control initial nucMLF axon guidance. We further show that two guidance molecules, transient axonal glycoprotein-1 (TAG-1) and laminin-α1, are essential for the initial directional extension of nucMLF axons and their subsequent convergence into a tight fascicle. Fixed tissue analysis shows that TAG-1 knockdown causes errors in nucMLF axon pathfinding similar to those seen in a laminin-α1 mutant. However, in vivo time-lapse imaging reveals that while some defects in dynamic growth cone behavior are similar, there are also defects unique to the loss of each gene. Loss of either TAG-1 or laminin-α1 causes nucMLF axons to extend into surrounding tissue in incorrect directions and reduces axonal growth rate, resulting in stunted nucMLF axons that fail to extend beyond the hindbrain. However, defects in axon-axon interactions were found only after TAG-1 knockdown, while defects in initial nucMLF axon polarity and excessive branching of nucMLF axons occurred only in laminin-α1 mutants. Conclusion: These results demonstrate how two guidance cues, TAG-1 and laminin-α1, influence the behavior of growth cones during axon pathfinding in vivo. Our data suggest that TAG-1 functions to allow growth cones to sense environmental cues and mediates positive axon-axon interactions. Laminin-α1 does not regulate axon-axon interactions, but does influence neuronal polarity and directional guidance. http://www.neuraldevelopment.com/content/3/1/6 Marc A Wolman, Vinoth K Sittaramane, Jeffrey J Essner, H Joseph Yost, Anand Chandrasekhar and Mary C Halloran Neural Development 2008, 3:6 2008-02-20 doi:10.1186/1749-8104-3-6 Neural Development 1749-8104 3 6 2008-02-20