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Neuron Oct 2004For decades, it has been suggested that complex neural wiring might be specified by extensive diversity in receptor isoforms. Dscam is a cell surface protein with 38,016... (Review)
Review
For decades, it has been suggested that complex neural wiring might be specified by extensive diversity in receptor isoforms. Dscam is a cell surface protein with 38,016 potential alternatively spliced isoforms in the fly nervous system. Remarkable binding studies now show that Dscam isoform diversity indeed results in an unprecedented level of recognition diversity, showing isoform-specific homophilic binding. In vivo studies have begun to suggest models for use of Dscam diversity in neuron-target recognition, axon fasciculation, and neuron self-recognition.
Topics: Animals; Cell Adhesion Molecules; Drosophila Proteins; Genetic Variation; Humans; Neurons; Protein Isoforms
PubMed: 15473961
DOI: 10.1016/j.neuron.2004.10.004 -
The Journal of Neuroscience : the... Jul 2000We have analyzed the role of the Slit family of repellent axon guidance molecules in the patterning of the axonal projections of retinal ganglion cells (RGCs) within the...
We have analyzed the role of the Slit family of repellent axon guidance molecules in the patterning of the axonal projections of retinal ganglion cells (RGCs) within the embryonic rat diencephalon and whether the slits can account for a repellent activity for retinal axons released by hypothalamus and epithalamus. At the time RGC axons extend over the diencephalon, slit1 and slit2 are expressed in hypothalamus and epithalamus but not in the lateral part of dorsal thalamus, a retinal target. slit3 expression is low or undetectable. The Slit receptors robo2, and to a limited extent robo1, are expressed in the RGC layer, as are slit1 and slit2. In collagen gels, axon outgrowth from rat retinal explants is biased away from slit2-transfected 293T cells, and the number and length of axons are decreased on the explant side facing the cells. In addition, in the presence of Slit2, overall axon outgrowth is decreased, and bundles of retinal axons are more tightly fasciculated. This action of Slit2 as a growth inhibitor of retinal axons and the expression patterns of slit1 and slit2 correlate with the fasciculation and innervation patterns of RGC axons within the diencephalon and implicate the Slits as components of the axon repellent activity associated with the hypothalamus and epithalamus. Our findings suggest that in vivo the Slits control RGC axon pathfinding and targeting within the diencephalon by regulating their fasciculation, preventing them or their branches from invading nontarget tissues, and steering them toward their most distal target, the superior colliculus.
Topics: Animals; Axons; Body Patterning; Diencephalon; Female; Gene Expression Regulation, Developmental; Gestational Age; Intercellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Pregnancy; Rats; Rats, Sprague-Dawley; Retina; Retinal Ganglion Cells; Visual Pathways
PubMed: 10864956
DOI: 10.1523/JNEUROSCI.20-13-04983.2000 -
Development (Cambridge, England) May 2014In gnathostome vertebrates, including fish, birds and mammals, peripheral nerves link nervous system, body and immediate environment by integrating efferent pathways...
In gnathostome vertebrates, including fish, birds and mammals, peripheral nerves link nervous system, body and immediate environment by integrating efferent pathways controlling movement apparatus or organ function and afferent pathways underlying somatosensation. Several lines of evidence suggest that peripheral nerve assembly involves instructive interactions between efferent and afferent axon types, but conflicting findings challenge this view. Using genetic modeling in zebrafish, chick and mouse we uncover here a conserved hierarchy of axon type-dependent extension and selective fasciculation events that govern peripheral nerve assembly, which recapitulates the successive phylogenetic emergence of peripheral axon types and circuits in the vertebrate lineage.
Topics: Animals; Axons; Chick Embryo; Chickens; Dermis; Mice; Motor Neurons; Neurons, Afferent; Neurons, Efferent; Peripheral Nerves; Zebrafish
PubMed: 24700820
DOI: 10.1242/dev.106211 -
Developmental Biology Feb 2015Sensory trigeminal growth cones innervate the cornea in a coordinated fashion during embryonic development. Polysialic acid (polySia) is known for its important roles...
Sensory trigeminal growth cones innervate the cornea in a coordinated fashion during embryonic development. Polysialic acid (polySia) is known for its important roles during nerve development and regeneration. The purpose of this work is to determine whether polySia, present in developing eyefronts and on the surface of sensory nerves, may provide guidance cues to nerves during corneal innervation. Expression and localization of polySia in embryonic day (E)5-14 chick eyefronts and E9 trigeminal ganglia were identified using Western blotting and immunostaining. Effects of polySia removal on trigeminal nerve growth behavior were determined in vivo, using exogenous endoneuraminidase (endoN) treatments to remove polySia substrates during chick cornea development, and in vitro, using neuronal explant cultures. PolySia substrates, made by the physical adsorption of colominic acid to a surface coated with poly-d-lysine (PDL), were used as a model to investigate functions of the polySia expressed in axonal environments. PolySia was localized within developing eyefronts and on trigeminal sensory nerves. Distributions of PolySia in corneas and pericorneal regions are developmentally regulated. PolySia removal caused defasciculation of the limbal nerve trunk in vivo from E7 to E10. Removal of polySia on trigeminal neurites inhibited neurite outgrowth and caused axon defasciculation, but did not affect Neural Cell Adhesion Molecule (NCAM) expression or Schwann cell migration in vitro. PolySia substrates in vitro inhibited outgrowth of trigeminal neurites and promoted their fasciculation. In conclusion, polySia is localized on corneal nerves and in their targeting environment during early developing stages of chick embryos. PolySias promote fasciculation of trigeminal axons in vivo and in vitro, whereas, in contrast, their removal promotes defasciculation.
Topics: Animals; Axons; Cell Movement; Cell Survival; Chick Embryo; Cornea; Embryonic Development; Fasciculation; Laminin; Neural Cell Adhesion Molecules; Neurites; Schwann Cells; Sensation; Sialic Acids; Trigeminal Nerve
PubMed: 25478909
DOI: 10.1016/j.ydbio.2014.11.020 -
The Journal of Neuroscience : the... Aug 2023Semaphorins and Plexins form ligand/receptor pairs that are crucial for a wide range of developmental processes from cell proliferation to axon guidance. The ability of...
Semaphorins and Plexins form ligand/receptor pairs that are crucial for a wide range of developmental processes from cell proliferation to axon guidance. The ability of semaphorins to act both as signaling receptors and ligands yields a multitude of responses. Here, we describe a novel role for Semaphorin-6D (Sema6D) and Plexin-A1 in the positioning and targeting of retinogeniculate axons. In or mutant mice of either sex, the optic tract courses through, rather than along, the border of the dorsal lateral geniculate nucleus (dLGN), and some retinal axons ectopically arborize adjacent and lateral to the optic tract rather than defasciculating and entering the target region. We find that Sema6D and Plexin-A1 act together in a dose-dependent manner, as the number of the ectopic retinal projections is altered in proportion to the level of Sema6D or Plexin-A1 expression. Moreover, using retinal electroporation of Sema6D or Plexin-A1 shRNA, we show that Sema6D and Plexin-A1 are both required in retinal ganglion cells for axon positioning and targeting. Strikingly, nonelectroporated retinal ganglion cell axons also mistarget in the tract region, indicating that Sema6D and Plexin-A1 can act non-cell-autonomously, potentially through axon-axon interactions. These data provide novel evidence for a dose-dependent and non-cell-autonomous role for Sema6D and Plexin-A1 in retinal axon organization in the optic tract and dLGN. Before innervating their central brain targets, retinal ganglion cell axons fasciculate in the optic tract and then branch and arborize in their target areas. Upon deletion of the guidance molecules Plexin-A1 or Semaphorin-6D, the optic tract becomes disorganized near and extends within the dorsal lateral geniculate nucleus. In addition, some retinal axons form ectopic aggregates within the defasciculated tract. Sema6D and Plexin-A1 act together as a receptor-ligand pair in a dose-dependent manner, and non-cell-autonomously, to produce this developmental aberration. Such a phenotype highlights an underappreciated role for axon guidance molecules in tract cohesion and appropriate defasciculation near, and arborization within, targets.
Topics: Animals; Mice; Axons; Ligands; Retinal Ganglion Cells; Semaphorins
PubMed: 37344233
DOI: 10.1523/JNEUROSCI.0072-22.2023 -
The Journal of Neuroscience : the... Mar 2015Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing...
Retina ganglion cell (RGC) axons grow along a stereotyped pathway undergoing coordinated rounds of fasciculation and defasciculation, which are critical to establishing proper eye-brain connections. How this coordination is achieved is poorly understood, but shedding of guidance cues by metalloproteinases is emerging as a relevant mechanism. Secreted Frizzled Related Proteins (Sfrps) are multifunctional proteins, which, among others, reorient RGC growth cones by regulating intracellular second messengers, and interact with Tolloid and ADAM metalloproteinases, thereby repressing their activity. Here, we show that the combination of these two functions well explain the axon guidance phenotype observed in Sfrp1 and Sfrp2 single and compound mouse mutant embryos, in which RGC axons make subtle but significant mistakes during their intraretinal growth and inappropriately defasciculate along their pathway. The distribution of Sfrp1 and Sfrp2 in the eye is consistent with the idea that Sfrp1/2 normally constrain axon growth into the fiber layer and the optic disc. Disheveled axon growth instead seems linked to Sfrp-mediated modulation of metalloproteinase activity. Indeed, retinal explants from embryos with different Sfrp-null alleles or explants overexpressing ADAM10 extend axons with a disheveled appearance, which is reverted by the addition of Sfrp1 or an ADAM10-specific inhibitor. This mode of growth is associated with an abnormal proteolytic processing of L1 and N-cadherin, two ADAM10 substrates previously implicated in axon guidance. We thus propose that Sfrps contribute to coordinate visual axon growth with a dual mechanism: by directly signaling at the growth cone and by regulating the processing of other relevant cues.
Topics: Animals; Axons; Female; Frizzled Receptors; Intercellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Retinal Ganglion Cells; Visual Pathways
PubMed: 25788689
DOI: 10.1523/JNEUROSCI.3304-13.2015 -
Neuron Aug 2014To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with...
To explore the link between bioenergetics and motor neuron degeneration, we used a computational model in which detailed morphology and ion conductance are paired with intracellular ATP production and consumption. We found that reduced ATP availability increases the metabolic cost of a single action potential and disrupts K+/Na+ homeostasis, resulting in a chronic depolarization. The magnitude of the ATP shortage at which this ionic instability occurs depends on the morphology and intrinsic conductance characteristic of the neuron. If ATP shortage is confined to the distal part of the axon, the ensuing local ionic instability eventually spreads to the whole neuron and involves fasciculation-like spiking events. A shortage of ATP also causes a rise in intracellular calcium. Our modeling work supports the notion that mitochondrial dysfunction can account for salient features of the paralytic disorder amyotrophic lateral sclerosis, including motor neuron hyperexcitability, fasciculation, and differential vulnerability of motor neuron subpopulations.
Topics: Action Potentials; Adenosine Triphosphate; Calcium; Energy Metabolism; Homeostasis; Models, Neurological; Motor Neurons; Nerve Degeneration; Potassium; Sodium
PubMed: 25088365
DOI: 10.1016/j.neuron.2014.07.001 -
Development (Cambridge, England) Oct 2003Early neuronal scaffold development studies suggest that initial neurons and their axons serve as guides for later neurons and their processes. Although this arrangement...
Early neuronal scaffold development studies suggest that initial neurons and their axons serve as guides for later neurons and their processes. Although this arrangement might aid axon navigation, the specific consequence(s) of such interactions are unknown in vivo. We follow forebrain commissure formation in living zebrafish embryos using timelapse fluorescence microscopy to examine quantitatively commissural axon kinetics at the midline: a place where axon interactions might be important. Although it is commonly accepted that commissural axons slow down at the midline, our data show this is only true for leader axons. Follower axons do not show this behavior. However, when the leading axon is ablated, follower axons change their midline kinetics and behave as leaders. Similarly, contralateral leader axons change their midline kinetics when they grow along the opposite leading axon across the midline. These data suggest a simple model where the level of growth cone exposure to midline cues and presence of other axons as a substrate shape the midline kinetics of commissural axons.
Topics: Animals; Axons; DNA-Binding Proteins; GATA2 Transcription Factor; Genes, Reporter; Kinetics; Nervous System; Recombinant Fusion Proteins; Transcription Factors; Zebrafish
PubMed: 12952902
DOI: 10.1242/dev.00713 -
Advances in Nutrition (Bethesda, Md.) May 2012The early stages of neurodevelopment in infants are crucial for establishing neural structures and synaptic connections that influence brain biochemistry well into... (Review)
Review
The early stages of neurodevelopment in infants are crucial for establishing neural structures and synaptic connections that influence brain biochemistry well into adulthood. This postnatal period of rapid neural growth is of critical importance for cell migration, neurite outgrowth, synaptic plasticity, and axon fasciculation. These processes thus place an unusually high demand on the intracellular pool of nutrients and biochemical precursors. Sialic acid (Sia), a family of 9-carbon sugar acids, occurs in large amounts in human milk oligosaccharides and is an essential component of brain gangliosides and sialylated glycoproteins, particularly as precursors for the synthesis of the polysialic acid (polySia) glycan that post-translationally modify the cell membrane-associated neural cell adhesion molecules (NCAM). Human milk is noteworthy in containing exceptionally high levels of Sia-glycoconjugates. The predominate form of Sia in human milk is N-acetylneuraminic acid (Neu5Ac). Infant formula, however, contains low levels of Sia consisting of both Neu5Ac and N-glycolyneuraminic acid (Neu5Gc). Current studies implicate Neu5Gc in several human inflammatory diseases. Polysialylated NCAM and neural gangliosides both play critical roles in mediating cell-to-cell interactions important for neuronal outgrowth, synaptic connectivity, and memory formation. A diet rich in Sia also increases the level of Sia in the brains of postnatal piglets, the expression level of 2 learning-related genes, and enhances learning and memory.
Topics: Animals; Brain; Cell Communication; Cognition; Gangliosides; Glycoconjugates; Humans; Infant; Infant Formula; Learning; Memory; Milk, Human; N-Acetylneuraminic Acid; Neural Cell Adhesion Molecules; Sialic Acids
PubMed: 22585926
DOI: 10.3945/an.112.001875 -
Developmental Biology Sep 2006The transcription factor cVax (Vax2) is expressed in the ventral neural retina and restricted expression is a prerequisite for at least three prominent aspects of...
The transcription factor cVax (Vax2) is expressed in the ventral neural retina and restricted expression is a prerequisite for at least three prominent aspects of retinal dorsal-ventral patterning: polarized expression of EphB/B-ephrin molecules, the retinotectal projection and the distribution of rod photoreceptors across the retina. In the chick retina, the fasciculation pattern of ganglion cell axons also differs between the dorsal and ventral eye. To investigate the molecular mechanisms involved, the nerve fiber layer was analyzed after retroviral misexpression of several factors known to regulate the positional specification of retinal ganglion cells. Forced cVax expression ventralized the fasciculation pattern and caused axon pathfinding errors near the optic disc. Ectopic expression of different ephrin molecules indicated that axon fasciculation is, at least in part, mediated by the EphB system. Finally, we report that retroviral misexpression of cVax increased the pool of EphA4 receptors phosphorylated on tyrosine residues and altered the guidance preference of nasal axons in vitro. These results identify novel functions for cVax in intraretinal axon fasciculation and pathfinding as well as suggest a mechanism to explain how restricted cVax expression may influence map formation along the dorso-ventral and antero-posterior axes of the optic tectum.
Topics: Animals; Axons; Body Patterning; Chick Embryo; Ephrin-A5; Ephrin-B1; Ephrin-B2; Ephrin-B3; Eye Proteins; Fasciculation; Gene Expression Regulation, Developmental; Homeodomain Proteins; Phosphorylation; Receptor, EphA4; Retina; Retinal Ganglion Cells; Retroviridae; T-Box Domain Proteins; Tyrosine
PubMed: 16769047
DOI: 10.1016/j.ydbio.2006.04.466