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C S Goodman

Publications and source records attributed to C S Goodman.

At least 55 records · Page 3Linked to original sources
PubMed1998

Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors.

The robo gene in Drosophila was identified in a large-scale mutant screen for genes that control the decision by axons to cross the CNS midline. In robo mutants, too many axons cross and recross the midline. Here we show that robo encodes an axon guidance receptor that defines a novel subfamily of immunoglobulin superfamily proteins that is highly conserved from fruit flies to mammals. For those axons that never cross the midline, Robo is expressed on their growth cones from the outset; for the majority of axons that do cross the midline, Robo is expressed at high levels on their growth cones only after they cross the midline. Transgenic rescue experiments reveal that Robo can function in a cell-autonomous fashion. Robo appears to function as the gatekeeper controlling midline crossing.

Amino Acid Sequence↗
PubMed1998

Many major CNS axon projections develop normally in the absence of semaphorin III.

The semaphorins constitute a large gene family of transmembrane and secreted molecules, many of which are expressed in the nervous system. Genetic studies in Drosophila have revealed a role for semaphorins in axon guidance and synapse formation, and several in vitro studies in mice have demonstrated a dramatic chemorepellent effect of semaphorin III (Sema III) on the axons of several populations of neurons. To investigate the function of Sema III during in vivo axon guidance in the mammalian CNS, we studied the development of axonal projections in mutant mice lacking Sema III. Projections were studied for which either the in vitro evidence suggests a role for Sema III in axon guidance (e.g., cerebellar mossy fibers, thalamocortical axons, or cranial motor neurons) or the in vivo expression suggests a role for Sema III in axon guidance (e.g., cerebellar Purkinje cells, neocortex). We find that many major axonal projections, including climbing fiber, mossy fiber, thalamocortical, and basal forebrain projections and cranial nerves, develop normally in the absence of Sema III. Despite its in vitro function and in vivo expression, it appears as if Sema III is not absolutely required for the formation of many major CNS tracts. Such data are consistent with recent models suggesting that axon guidance is controlled by a balance of forces resulting from multiple guidance cues. Our data lead us to suggest that if Sema III functions in part to guide the formation of major axonal projections, then it does so in combination with both other semaphorins and other families of guidance molecules.

Animals↗
PubMed1998

Dosage-sensitive and complementary functions of roundabout and commissureless control axon crossing of the CNS midline.

commissureless and roundabout lead to complementary mutant phenotypes in which either too few or too many axons cross the midline. The robo;comm double-mutant phenotype is identical to robo alone, suggesting that in the absence of robo, comm is no longer required. Comm is expressed on midline cells; Robo is expressed in a dynamic fashion on growth cones and appears to function as an axon guidance receptor. robo function is dosage-sensitive. Overexpression of comm is also dosage-sensitive and leads to a phenotype identical to robo loss-of-function. Comm controls Robo expression; increasing Comm leads to a reduction of Robo protein. The levels of Comm and Robo appear to be tightly regulated to assure that only certain growth cones cross the midline and that those growth cones that do cross never do so again.

Animals↗
PubMed1998

Postsynaptic PKA controls quantal size and reveals a retrograde signal that regulates presynaptic transmitter release in Drosophila.

Two distinct mechanisms regulate synaptic efficacy at the Drosophila neuromuscular junction (NMJ): a PKA-dependent modulation of quantal size and a retrograde regulation of presynaptic release. Postsynaptic expression of a constitutively active PKA catalytic subunit decreases quantal size, whereas overexpression of a mutant PKA regulatory subunit (inhibiting PKA activity) increases quantal size. Increased PKA activity also decreases the response to direct iontophoresis of glutamate onto postsynaptic receptors. The PKA-dependent modulation of quantal size requires the presence of the muscle-specific glutamate receptor DGluRIIA, since PKA-dependent modulation of quantal size is lost in homozygous viable DGluRIIA- mutants. Furthermore, elevated postsynaptic PKA reduces the quantal amplitude and the time constant of miniature excitatory junctional potential (mEJP) decay to values that are nearly identical to those observed in DGluRIIA mutants. The PKA-dependent reduction in quantal size is accompanied developmentally by an increase in presynaptic quantal content, indicating the presence of a retrograde signal that regulates presynaptic release.

Animals↗
PubMed1998

Wrapper, a novel member of the Ig superfamily, is expressed by midline glia and is required for them to ensheath commissural axons in Drosophila.

The midline glia are specialized, nonneuronal cells at the midline of the Drosophila central nervous system (CNS). During development, the midline glia provide guidance cues for extending axons. At the same time, they migrate and help separate the two axon commissures. They then wrap around and ensheath the commissural axons. In many segments, a few of the glia do not enwrap the axons, and these cells die. The wrapper gene encodes a novel member of the immunoglobulin (Ig) superfamily. Wrapper protein is expressed specifically on the surface of midline glia. In wrapper mutant embryos, the midline glia express their normal guidance cues and migrate normally. However, they do not ensheath the commissural axons, and as a result, the glia die. In the absence of Wrapper, the two axon commissures are not properly separated.

Amino Acid Sequence↗
PubMed1998

Semaphorins III and IV repel hippocampal axons via two distinct receptors.

The semaphorins are the largest family of repulsive axon guidance molecules. Secreted semaphorins bind neuropilin receptors and repel sensory, sympathetic and motor axons. Here we show that CA1, CA3 and dentate gyrus axons from E15-E17 mouse embryo explants are selectively repelled by entorhinal cortex and neocortex. The secreted semaphorins Sema III and Sema IV and their receptors Neuropilin-1 and -2 are expressed in the hippocampal formation during appropriate stages. Sema III and Sema IV strongly repel CA1, CA3 and dentate gyrus axons; entorhinal axons are only repelled by Sema III. An antibody against Neuropilin-1 blocks the repulsive action of Sema III and the entorhinal cortex, but has no effect on Sema IV-induced repulsion. Thus, chemorepulsion plays a role in axon guidance in the hippocampus, secreted semaphorins are likely to be responsible for this action, and the same axons can be repelled by two distinct semaphorins via two different receptors.

Animals↗
PubMed1998

In vitro and skin testing for allergy: comparable clinical utility and costs.

Controversy exists concerning the appropriate use of skin testing and in vitro testing for the diagnosis of allergy, particularly inhalant allergy. Earlier comparisons of skin testing and in vitro testing concluded that skin testing had superior accuracy at lower expense. In light of new developments with in vitro allergy testing, however, this issue should be reconsidered. A review of the recent scientific literature indicates that in vitro and skin testing are highly correlated. However, without the existence of an independent gold standard for inhalant allergy, it is not possible to determine which test is more accurate. The accuracy of either test can be compromised if conducted using different protocols or having insufficient quality control. Given their respective trajectories for technological advancement, quantification, and quality control, in vitro testing may offer the more standardized approach. Although the cost per test of in vitro testing remains greater than that of skin testing, the per-patient costs of the two modalities appear to be comparable, given the greater number of allergens typically used in skin testing. In summary, both skin testing and in vitro testing are acceptable as frontline diagnostic tools.

Cost-Benefit Analysis↗
PubMed1997

Genetic analysis of myoblast fusion: blown fuse is required for progression beyond the prefusion complex.

The events of myoblast fusion in Drosophila are dissected here by combining genetic analysis with light and electron microscopy. We describe a new and essential intermediate step in the process, the formation of a prefusion complex consisting of "paired vesicles." These pairs of vesicles from different cells align with each other across apposed plasma membranes. This prefusion complex resolves into dense membrane plaques between apposed cells; these cells then establish cytoplasmic continuity by fusion of small areas of plasma membrane followed by vesiculation of apposed membranes. Different steps in this process are specifically blocked by mutations in four genes required for myoblast fusion. One of these genes, blown fuse, encodes a novel cytoplasmic protein expressed in unfused myoblasts that is essential for progression beyond the prefusion complex stage.

Amino Acid Sequence↗
PubMed1997

Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III.

Semaphorins are a large family of secreted and transmembrane proteins, several of which are implicated in repulsive axon guidance. Neuropilin (neuropilin-1) was recently identified as a receptor for Collapsin-1/Semaphorin III/D (Sema III). We report the identification of a related protein, neuropilin-2, whose mRNA is expressed by developing neurons in a pattern largely, though not completely, nonoverlapping with that of neuropilin-1. Unlike neuropilin-1, which binds with high affinity to the three structurally related semaphorins Sema III, Sema E, and Sema IV, neuropilin-2 shows high affinity binding only to Sema E and Sema IV, not Sema III. These results identify neuropilins as a family of receptors (or components of receptors) for at least one semaphorin subfamily. They also suggest that the specificity of action of different members of this subfamily may be determined by the complement of neuropilins expressed by responsive cells.

Animals↗
PubMed1997

Genetic analysis of the mechanisms controlling target selection: target-derived Fasciclin II regulates the pattern of synapse formation.

In Drosophila, motoneuron growth cones initially probe many potential muscle targets but later withdraw most of these contacts to form stereotypic synapses with only one or a few muscles. Prior to synapse formation, Fasciclin II (Fas II) is expressed at low levels on muscle. During synapse formation, Fas II concentrates at the synapse and disappears from the rest of the muscle. We previously showed that Fas II is required both pre- and postsynaptically for synaptic stabilization. Here, we show that the differential expression of target-derived Fas II has a profound influence on the patterning of synapse formation. A transient increase in muscle Fas II stabilizes growth cone contacts and leads to novel synapses that are functional and stable; targets that normally receive two inputs can now receive up to six inputs. Changing the relative levels of Fas II on neighboring muscles leads to dramatic shifts in target selection.

Animals↗
PubMed1997

Synaptic clustering of Fascilin II and Shaker: essential targeting sequences and role of Dlg.

Previous studies have shown that both the Fasciclin II (Fas II) cell adhesion molecule and the Shaker potassium channel are localized at the Drosophila neuromuscular junction, where they function in the growth and plasticity of the synapse. Here, we use the GAL4-UAS system to drive expression of the chimeric proteins CD8-Fas II and CD8-Shaker and show that the C-terminal sequences of both Fas II and Shaker are necessary and sufficient to drive the synaptic localization of a heterologous protein. Moreover, we show that the PDZ-containing protein Discs-Large (Dlg) controls the localization of these proteins, most likely through a direct interaction with their C-terminal amino acids. Finally, transient expression studies show that the pathway these proteins take to the synapse involves either an active clustering or a selective stabilization in the synaptic membrane.

Amino Acid Sequence↗
PubMed1997

Genetic analysis of glutamate receptors in Drosophila reveals a retrograde signal regulating presynaptic transmitter release.

Postsynaptic sensitivity to glutamate was genetically manipulated at the Drosophila neuromuscular junction (NMJ) to test whether postsynaptic activity can regulate presynaptic function during development. We cloned the gene encoding a second muscle-specific glutamate receptor, DGluRIIB, which is closely related to the previously identified DGluRIIA and located adjacent to it in the genome. Mutations that eliminate DGluRIIA (but not DGluRIIB) or transgenic constructs that increase DGluRIIA expression were generated. When DGluRIIA is missing, the response of the muscle to a single vesicle of transmitter is substantially decreased. However, the response of the muscle to nerve stimulation is normal because quantal content is significantly increased. Thus, a decrease in postsynaptic receptors leads to an increase in presynaptic transmitter release, indicating that postsynaptic activity controls a retrograde signal that regulates presynaptic function.

Amino Acid Sequence↗
PubMed1996

The Drosophila beaten path gene encodes a novel secreted protein that regulates defasciculation at motor axon choice points.

In the Drosophila embryo, at specific choice points along the major motor nerves, subsets of motor axons defasciculate and then steer into their muscle target regions. Here we describe the analysis of beaten path (beat), a gene required for the selective defasciculation of motor axons at these choice points. In beat mutant embryos, motor axons fail to defasciculate and bypass their targets. This phenotype is suppressed by mutations in FasII and conn, two genes encoding cell adhesion molecules expressed on motor axons, suggesting that beat provides an antiadhesive function. beat encodes a novel secreted protein that is expressed by motoneurons during outgrowth. Rescue and ectopic expression experiments support the model that Beat protein is secreted by motor axons where it functions to regulate their selective defasciculation at specific choice points.

Amino Acid Sequence↗
PubMed1996

The molecular biology of axon guidance.

Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.

Animals↗
PubMed1996

The cell surface metalloprotease/disintegrin Kuzbanian is required for axonal extension in Drosophila.

It has long been suspected that proteolytic activity associated with advancing growth cones may be required for axon extension. We have isolated mutations in the kuzbanian (kuz) gene, which is expressed in the nervous system and encodes a putative zinc metalloprotease with a disintegrin domain. Drosophila embryos with loss-of-function mutations in kuz have dramatic defects in the development of central nervous system axon pathways, with many axons stalling and failing to extend through the nerve cord. This phenotype is rescued by panneural expression of kuz mRNA in the embryo. These results show that the Kuz metalloprotease is required for axon extension, suggesting a requirement for proteolytic activity at the growth cone surface.

Animals↗