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1.
Binding of DCC by netrin-1 to mediate axon guidance independent of adenosine A2B receptor activation
Netrins stimulate and orient axon growth through a mechanism requiring receptors of the DCC family. It has been unclear, however, whether DCC proteins are involved directly in signaling or are mere accessory proteins in a receptor complex. Further, although netrins bind cells expressing DCC, direct binding to DCC has not been demonstrated. Here we show that netrin-1 binds DCC and that the DCC cytoplasmic domain fused to a heterologous receptor ectodomain can mediate guidance through a mechanism involving derepression of cytoplasmic domain multimerization. Activation of the adenosine A2B receptor, proposed to contribute to netrin effects on axons, is not required for rat commissural axon outgrowth or Xenopus spinal axon attraction to netrin-1. Thus, DCC plays a central role in netrin signaling of axon growth and guidance independent of A2B receptor activation. 相似文献
2.
The axonal chemoattractant netrin-1 guides spinal commissural axons by activating its receptor DCC (Deleted in Colorectal Cancer). We have found that chemical inhibitors of metalloproteases potentiate netrin-mediated axon outgrowth in vitro. We have also found that DCC is a substrate for metalloprotease-dependent ectodomain shedding, and that the inhibitors block proteolytic processing of DCC and cause an increase in DCC protein levels on axons within spinal cord explants. Thus, potentiation of netrin activity by inhibitors may result from stabilization of DCC on the axons, and proteolytic activity may regulate axon migration by controlling the number of functional extracellular axon guidance receptors. 相似文献
3.
A protein induced during nerve growth (GAP-43) is a major component of growth-cone membranes 总被引：24，自引：0，他引：24
J H Skene R D Jacobson G J Snipes C B McGuire J J Norden J A Freeman 《Science (New York, N.Y.)》1986,233(4765):783-786
Growth cones are specialized structures that form the distal tips of growing axons. During both normal development of the nervous system and regeneration of injured nerves, growth cones are essential for elongation and guidance of growing axons. Developmental and regenerative axon growth is frequently accompanied by elevated synthesis of a protein designated GAP-43. GAP-43 has now been found to be a major component of growth-cone membranes in developing rat brains. Relative to total protein, GAP-43 is approximately 12 times as abundant in growth-cone membranes as in synaptic membranes from adult brains. Immunohistochemical localization of GAP-43 in frozen sections of developing brain indicates that the protein is specifically associated with neuropil areas containing growth cones and immature synaptic terminals. The results support the proposal that GAP-43 plays a role in axon growth. 相似文献
4.
Fricke C Lee JS Geiger-Rudolph S Bonhoeffer F Chien CB 《Science (New York, N.Y.)》2001,292(5516):507-510
As growing retinotectal axons navigate from the eye to the tectum, they sense guidance molecules distributed along the optic pathway. Mutations in the zebrafish astray gene severely disrupt retinal axon guidance, causing anterior-posterior pathfinding defects, excessive midline crossing, and defasciculation of the retinal projection. Eye transplantation experiments show that astray function is required in the eye. We identify astray as zebrafish robo2, a member of the Roundabout family of axon guidance receptors. Retinal ganglion cells express robo2 as they extend axons. Thus, robo2 is required for multiple axon guidance decisions during establishment of the vertebrate visual projection. 相似文献
5.
Human amnion membrane serves as a substratum for growing axons in vitro and in vivo 总被引：13，自引：0，他引：13
G E Davis S N Blaker E Engvall S Varon M Manthorpe F H Gage 《Science (New York, N.Y.)》1987,236(4805):1106-1109
The epithelial cell layer of human amnion membrane can be removed while the basement membrane and stromal surfaces remain morphologically intact. Such a preparation has been used as a substratum for the in vitro culture of dissociated neurons. Embryonic motor neurons from chick ciliary ganglion attached to both surfaces but grew extensive neurites only on the basement membrane. On cross sections of rolled amnion membranes, regenerating axons of cultured neurons were guided along pathways of basement membrane that were immunoreactive with an antibody to laminin. In addition, when rolled amnion membranes were implanted into a lesion cavity between the rat septum and hippocampus, cholinergic neurons extended axons through the longitudinally oriented implant into the hippocampus. Thus, this amnion preparation can serve as a bridge to promote axonal regeneration in vivo in damaged adult brain. 相似文献
6.
Osterloh JM Yang J Rooney TM Fox AN Adalbert R Powell EH Sheehan AE Avery MA Hackett R Logan MA MacDonald JM Ziegenfuss JS Milde S Hou YJ Nathan C Ding A Brown RH Conforti L Coleman M Tessier-Lavigne M Züchner S Freeman MR 《Science (New York, N.Y.)》2012,337(6093):481-484
Axonal and synaptic degeneration is a hallmark of peripheral neuropathy, brain injury, and neurodegenerative disease. Axonal degeneration has been proposed to be mediated by an active autodestruction program, akin to apoptotic cell death; however, loss-of-function mutations capable of potently blocking axon self-destruction have not been described. Here, we show that loss of the Drosophila Toll receptor adaptor dSarm (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) cell-autonomously suppresses Wallerian degeneration for weeks after axotomy. Severed mouse Sarm1 null axons exhibit remarkable long-term survival both in vivo and in vitro, indicating that Sarm1 prodegenerative signaling is conserved in mammals. Our results provide direct evidence that axons actively promote their own destruction after injury and identify dSarm/Sarm1 as a member of an ancient axon death signaling pathway. 相似文献
7.
In Caenorhabditis elegans, the gonad acquires two U-shaped arms by the directed migration of its distal tip cells (DTCs) along the body wall basement membranes. Correct migration of DTCs requires the mig-17 gene, which encodes a member of the metalloprotease-disintegrin protein family. The MIG-17 protein is secreted from muscle cells of the body wall and localizes in the basement membranes of gonad. This localization is dependent on the disintegrin-like domain of MIG-17 and its catalytic activity. These results suggest that the MIG-17 metalloprotease directs migration of DTCs by remodeling the basement membrane. 相似文献
8.
Organization of ion channels in the myelinated nerve fiber 总被引：8，自引：0，他引：8
The functional organization of the mammalian myelinated nerve fiber is complex and elegant. In contrast to nonmyelinated axons, whose membranes have a relatively uniform structure, the mammalian myelinated axon exhibits a high degree of regional specialization that extends to the location of voltage-dependent ion channels within the axon membrane. Sodium and potassium channels are segregated into complementary membrane domains, with a distribution reflecting that of the overlying Schwann or glial cells. This complexity of organization has important implications for physiology and pathophysiology, particularly with respect to the development of myelinated fibers. 相似文献
9.
Jen JC Chan WM Bosley TM Wan J Carr JR Rüb U Shattuck D Salamon G Kudo LC Ou J Lin DD Salih MA Kansu T Al Dhalaan H Al Zayed Z MacDonald DB Stigsby B Plaitakis A Dretakis EK Gottlob I Pieh C Traboulsi EI Wang Q Wang L Andrews C Yamada K Demer JL Karim S Alger JR Geschwind DH Deller T Sicotte NL Nelson SF Baloh RW Engle EC 《Science (New York, N.Y.)》2004,304(5676):1509-1513
The mechanisms controlling axon guidance are of fundamental importance in understanding brain development. Growing corticospinal and somatosensory axons cross the midline in the medulla to reach their targets and thus form the basis of contralateral motor control and sensory input. The motor and sensory projections appeared uncrossed in patients with horizontal gaze palsy with progressive scoliosis (HGPPS). In patients affected with HGPPS, we identified mutations in the ROBO3 gene, which shares homology with roundabout genes important in axon guidance in developing Drosophila, zebrafish, and mouse. Like its murine homolog Rig1/Robo3, but unlike other Robo proteins, ROBO3 is required for hindbrain axon midline crossing. 相似文献
10.
Insulin receptors are abundant in the central nervous system, but their roles remain elusive. Here we show that the insulin receptor functions in axon guidance. The Drosophila insulin receptor (DInR) is required for photoreceptor-cell (R-cell) axons to find their way from the retina to the brain during development of the visual system. DInR functions as a guidance receptor for the adapter protein Dock/Nck. This function is independent of Chico, the Drosophila insulin receptor substrate (IRS) homolog. 相似文献
11.
Astrocytes block axonal regeneration in mammals by activating the physiological stop pathway 总被引：15，自引：0，他引：15
Regenerating sensory axons in the dorsal roots of adult mammals are stopped at the junction between the root and spinal cord by reactive astrocytes. Do these cells stop axonal elongation by activating the physiological mechanisms that normally operate to stop axons during development, or do they physically obstruct the elongating axons? In order to distinguish these possibilities, the cytology of the axon tips of regenerating axons that were stopped by astrocytes was compared with the axon tips that were physically obstructed at a cul-de-sac produced by ligating a peripheral nerve. The terminals of the physically obstructed axon tips were distended with neurofilaments and other axonally transported structures that had accumulated when the axons stopped elongating. By contrast, neurofilaments did not accumulate in the tips of regenerating axons that were stopped by spinal cord astrocytes at the dorsal root transitional zone. These axo-glial terminals resembled the terminals that axons make on target neurons during normal development. On the basis of these observations, astrocytes appear to stop axons from regenerating in the mammalian spinal cord by activating the physiological stop pathway that is built into the axon and that normally operates when axons form stable terminals on target cells. 相似文献
12.
In the mammalian cortex, it is generally assumed that the output information of neurons is encoded in the number and the timing of action potentials. Here, we show, by using direct patchclamp recordings from presynaptic hippocampal mossy fiber boutons, that axons transmit analog signals in addition to action potentials. Excitatory presynaptic potentials result from subthreshold dendritic synaptic inputs, which propagate several hundreds of micrometers along the axon and modulate action potential-evoked transmitter release at the mossy fiber-CA3 synapse. This combined analog and action potential coding represents an additional mechanism for information transmission in a major hippocampal pathway. 相似文献
13.
Garfish olfactory nerve: easily accessible source of numerous long, homogeneous, nonmyelinated axons 总被引：8，自引：0，他引：8
D M Easton 《Science (New York, N.Y.)》1971,172(986):952-955
The olfactory nerve of the garfish, Lepisosteus, is about 1 millimeter in diameter and about 20 centimeters long, depending on the size of the fish; it is easily prepared by breaking off successive scored segments of the rostrum. It consists of a relatively homogeneous population of about 10(7) nonmyelineated nerve fibers, each about 0.24 micrometer in diameter. In most other nerves each fiber is separated from all others by an enfolding Schwann cell, but in the olfactory nerve the fibers are directly in contact with one another in groups of several hundred fibers. The Schwann cell, not directly concerned with propagation of the nerve impulse, forms a thin layer at the periphery of the group and makes up a small proportion of the total cellular material. The volume of axon cytoplasm is about five times greater than that of Schwann cell cytoplasm, and the axon surface is about 30 times the Schwann cell surface. The ratio of surface to volume for axons of a typical olfactory nerve is about 5400 times that for the squid axon of the same diameter. The large proportion of axonal membrane recommends this nerve for use in chemical and physical studies of properties of axon membranes. 相似文献
14.
Neuronal axons connect to multiple target cells through the formation of collateral branches, but the mechanisms that regulate this process are largely unknown. We show that BAM-2, a neurexin-related transmembrane protein, is required for development of VC motoneuron branches in the worm Caenorhabditis elegans. Expression analysis and ectopic expression experiments suggest that BAM-2 functions as a branch termination cue and reveal a mechanism for selective control of branches that sprout off a primary axon. 相似文献
15.
Odorant receptor-derived cAMP signals direct axonal targeting 总被引：1，自引：0，他引：1
In mammals, odorant receptors (ORs) direct the axons of olfactory sensory neurons (OSNs) toward targets in the olfactory bulb. We show that cyclic adenosine monophosphate (cAMP) signals that regulate the expression of axon guidance molecules are essential for the OR-instructed axonal projection. Genetic manipulations of ORs, stimulatory G protein, cAMP-dependent protein kinase, and cAMP response element-binding protein shifted the axonal projection sites along the anteriorposterior axis in the olfactory bulb. Thus, it is the OR-derived cAMP signals, rather than direct action of OR molecules, that determine the target destinations of OSNs. 相似文献
16.
Chapman B 《Science (New York, N.Y.)》2000,287(5462):2479-2482
In the adult mammal, retinal ganglion cell axon arbors are restricted to eye-specific layers in the lateral geniculate nucleus. Blocking neuronal activity early in development prevents this segregation from occurring. To test whether activity is also required to maintain eye-specific segregation, ganglion cell activity was blocked after segregation was established. This caused desegregation, so that both eyes' axons became concentrated in lamina A, normally occupied only by contralateral afferents. These results show that an activity-dependent process is necessary for maintaining eye-specific segregation and suggest that activity-independent cues may favor lamina A as the target for arborization of afferents from both eyes. 相似文献
17.
Regulated cleavage of a contact-mediated axon repellent 总被引：2，自引：0，他引：2
Contact-mediated axon repulsion by ephrins raises an unresolved question: these cell surface ligands form a high-affinity multivalent complex with their receptors present on axons, yet rather than being bound, axons can be rapidly repelled. We show here that ephrin-A2 forms a stable complex with the metalloprotease Kuzbanian, involving interactions outside the cleavage region and the protease domain. Eph receptor binding triggered ephrin-A2 cleavage in a localized reaction specific to the cognate ligand. A cleavage-inhibiting mutation in ephrin-A2 delayed axon withdrawal. These studies reveal mechanisms for protease recognition and control of cell surface proteins, and, for ephrin-A2, they may provide a means for efficient axon detachment and termination of signaling. 相似文献
18.
Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A(1) receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring. 相似文献
19.
Park KK Liu K Hu Y Smith PD Wang C Cai B Xu B Connolly L Kramvis I Sahin M He Z 《Science (New York, N.Y.)》2008,322(5903):963-966
The failure of axons to regenerate is a major obstacle for functional recovery after central nervous system (CNS) injury. Removing extracellular inhibitory molecules results in limited axon regeneration in vivo. To test for the role of intrinsic impediments to axon regrowth, we analyzed cell growth control genes using a virus-assisted in vivo conditional knockout approach. Deletion of PTEN (phosphatase and tensin homolog), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, in adult retinal ganglion cells (RGCs) promotes robust axon regeneration after optic nerve injury. In wild-type adult mice, the mTOR activity was suppressed and new protein synthesis was impaired in axotomized RGCs, which may contribute to the regeneration failure. Reactivating this pathway by conditional knockout of tuberous sclerosis complex 1, another negative regulator of the mTOR pathway, also leads to axon regeneration. Thus, our results suggest the manipulation of intrinsic growth control pathways as a therapeutic approach to promote axon regeneration after CNS injury. 相似文献
20.
Transport of protein by goldfish optic nerve fibers 总被引：4，自引：0，他引：4
B Grafstein 《Science (New York, N.Y.)》1967,157(785):196-198
After tritiated leucine was injected into the eye of goldfish, radio-active protein synthesized by the ganglion cell bodies moved down the optic axons at an average rate of 0.4 mm per day. Radioautograms of the optic tectum in which these axons end show that, as early as 24 hours after the injection, before the radioactivity in the tectal layer containing the optic axons had risen above background level, the layer containing the axon terminals was already heavily labeled. The radioactivity in the terminals reached a maximum about 48 hours after the injection and remained approximately constant for at least 23 days thereafter, whereas the radioactivity in the fiber layer increased significantly during the same interval, as the slowly moving protein component entered it. Thus there appears to be a special mechanism for rapid transport of protein from the cell body to the synaptic terminals, as well as a slower movement of protein down the axon. 相似文献