Neuronal Guidance

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analysis of these molecules via mutagenesis forms the third major area within Drosophila neurogenetics. Four types of guidance mechanisms are used: chemorepulsion in which the secreted semaphorins and netrins are prevalent; chemoattraction, in which the

bifunctional netrins play an important role; and the shorter range cues of contact attraction and repulsion, which utilize molecules such as the cadherins and the transmembrane semaphorins, respectively. A detailed description of the mechanisms of axon pathfinding can be found in the article on Neuronal Guidance.

Further Reading

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Baker NE (2000) Notch signalling in the nervous system. Pieces still missing from the puzzle. Bioessays 22: 264±273. Dubnau J and Tully T (1998) Gene discovery in Drosophila: New insights for learning and memory. Annual Review of Neuroscience 21: 407±444. Goodwin SF (1999) Molecular neurogenetics of sexual differentiation and behaviour. Current Opinion in Neurobiology 9: 759±765. Greenspan RJ (1997) A kinder, gentler genetic analysis of behavior: dissection gives way to modulation. Current Opinion in Neurobiology 7: 805±811. Hall JC (1994) The mating of a fly. Science 264: 1702±1714. Heisenberg M (1997) Genetic approach to neuroethology. Bioessays 19: 1065±1073. Tessier-Lavigne M and Goodman CS (1996) The molecular biology of axon guidance. Science 274: 1123±1133.

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See also: Behavioral Genetics; Benzer, Seymour; Clock Mutants; Neuronal Guidance; Neuronal Specification

Neuron/Cell Degeneration See: Cell/Neuron Degeneration

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Figure 2 (A) The Notch signal transduction pathway. The core pathway has four main components: a transmembrane ligand, Delta (D1); a transmembrane receptor, Notch (N); a transcription factor, Suppressor of hairless (Su(H)); and Enhancer of split (E(spl)). Initially, Su(H) is tethered to the cell membrane by interactions with the intracellular portion of Notch. Activation of the pathway is initiated by the binding of Delta to the Notch receptor on an adjacent cell. This interaction results in the nuclear localization of Su(H) and possibly an intracellular portion of Notch (ICD). Nuclear Su(H), possibly in association with the Notch ICD, activates the transcription of the E(spl) genes. (B) Lateral inhibition and Notch/Delta signaling. All cells of the proneural cluster initially express Achaete-Scute (AS-C) genes, Notch, and Delta. After binding of the Delta ligand to Notch and expression of E(spl) genes, the E(spl) proteins inhibit the AS-C products. The level of Delta transcription is controlled by AS-C proteins, thus closing the feedback loop between Notch and Delta.

Neuronal Guidance S G Clark Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0893

Overview The nervous system provides a communication network for an organism and is comprised of specialized cells, called neurons, that exchange information through synaptic connections. Neurons project axons during development that migrate long distances along stereotypic pathways to find their appropriate targets and establish the initial connectivity of the nervous system. The trajectory of an individual axon is determined by the motile tip of the axon, the growth cone, responding to the appropriate spatial signals along its route. These signals include cell surface molecules and extracellular matrix molecules that provide

Neuronal Guidance 1319 short-range guidance or local guidance cues as well as secreted molecules that diffuse from their source and provide long-range or global guidance information. These signals can act to attract as well as to repel a migrating growth cone and, through their combined action, these signals orchestrate correct axon outgrowth and pathfinding. Several guidance molecules have been identified, and current efforts are directed toward further understanding the molecular mechanisms underlying axon guidance.

Historical background A little over 100 years ago, RamoÂn y Cajal (1893) discovered the motile tips of projecting axons, which he named growth cones, and observed that they often take roundabout routes to reach their targets. He suggested that growth cones function in axon guidance; further experimental evidence supporting his hypothesis was provided later by Harrison (1910) and Speidel (1941). Although alternative models for the establishment of neuronal connectivity were prevalent during the 1930s and 1940s, the work of Sperry in the 1950s firmly reestablished the notion that neuronal connectivity is generated by the directed migration of axons. From axon regeneration studies in amphibians and related experiments, Sperry (1963) postulated the `chemoaffinity theory,' which proposed the existence of specific surface markers that growth cones use for both pathway and target recognition. More recent studies in various model systems, including vertebrates, insects, and nematodes, have clearly established that axon pathfinding is highly specific and that common guidance mechanisms are conserved in all organisms. These studies have also led to a greater understanding of the cellular and molecular basis of axonal guidance.

Cellular Sources of Guidance Information Specific cells or groups of cells along the path of an extending axon provide guidance cues directing the axon to its final target. These cells are called guidepost cells in insects and act as intermediate targets for the migrating growth cone. The growth cone navigates to each intermediate target, one after the other, to reach its ultimate destination. Thus, the final trajectory of an individual axon, which can be long and complex, is composed of many short, sequential segments that are perhaps a few hundred microns in length. Although guidepost cells are important for correct pathfinding, additional cues that are provided by other cells in the axon's environment are essential also.

Many growth cones extend along preexisting axons for all or part of their migration. The first axon in a nerve tract is called the pioneer axon and latergrowing axons can bundle or fasciculate with the pioneer to form a nerve tract. Axons are highly organized within a nerve bundle: A particular follower axon will always associate with a specific preexisting axon in the bundle. The selective affinity of axons within a nerve bundle has suggested that different types of axons have qualitative differences or labels that allow for the recognition of specific axon pathways. The elimination of a pioneer axon often causes errors in the growth of the followers, indicating that they are important for the initial assembly and organization of nerve tracts. However, they are not absolutely required, as followers can partially compensate for their loss and form nerve tracts later in development.

Attractive and Repulsive Guidance Forces and Target Recognition Four types of guidance forces act in concert to guide growth cone migrations: short-range (local) cues and long-range (diffusible) cues, each of which can be either attractive or repulsive. Short-range guidance involves the direct interaction of the growth cone with molecules on the surface of cells or in the surrounding extracellular matrix. Growth cones prefer to extend on an attractive or permissive substrate. The selective fasciculation of an axon within a nerve bundle is an example of an attractive, short-range interaction. Local repulsive or inhibitory cues can act to channel the growth of axons and prevent them from straying from their correct course or from extending past their target. Some guidance cues are released or secreted from their source and can diffuse to establish a gradient within the surrounding environment. These longrange, diffusible signals (chemoattractants and chemorepellents) can provide global and position-dependent guidance information. Chemoattractants, which can be derived from the target or an intermediate target, direct the growth of the axon towards their source, whereas chemorepellents promote or redirect axon growth away from their source as well as cause axon growth to stall or stop. The coordinated, collective action of these four guidance forces steers the growth cone along its appropriate path to its target. Some neurons will extend axons along a common pathway to reach a shared target consisting of an array of many neurons, and each arriving axon will make a unique connection within that array. For example, in the vertebrate visual system, retinal ganglion cells make an orderly projection

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onto the optic tectum in fish, amphibians, and birds or the superior colliculus in mammals. Target recognition involves two mechanisms: topographic maps of graded cues and unique tags marking different targets. In the visual system, several gradients of both ligands and receptors define a topographic map that provides positional information for the formation of correct neuronal connections. In other, less complex contexts, individual axons can recognize specific cellular labels expressed by their target.

Guidance Molecules The molecular characterization of several guidance signals and their receptors revealed that guidance molecules and their functions are highly conserved across species. For example, netrins, which are secreted laminin-related signaling molecules, have been discovered in worms, flies, frogs, fish, birds, and mammals and act in conserved signaling pathways in all these organisms. A netrin is an example of a bifunctional signal, as it can act to attract as well as to repel axon growth. Whether netrin attracts or repels an individual growth cone depends on the types of netrin receptors expressed by that neuron and upon the substrate that the axon is growing. Some types of signals, such as the semaphorin family, contain both cell surface and diffusible members that are implicated in short- and long-range guidance, respectively. Thus, depending on the specific context, the same or related molecules can mediate more than one of the four guidance forces described earlier. Guidance signals and their receptors share sequence and structural motifs with extracellular matrix and cell adhesion molecules. Two major families of cell adhesion molecules have been identified: the immunoglobulin (Ig) gene superfamily and the cadherin superfamily, which contain both transmembrane and lipid-anchored proteins. The extracellular region of the Ig proteins consists of tandem arrays of Ig and fibronectin type III domains. Many neural cell adhesion molecules and guidance receptors are transmembrane proteins and members of the Ig superfamily. The intracellular region of some guidance receptors contains a protein tyrosine kinase or protein tyrosine phosphatase domain, and their signaling function depends, at least in part, on these catalytic activities. Other receptors lack an obvious catalytic domain and presumably signal via the association of other molecules. In summary, axon guidance is highly specific and conserved in both form and function in all organisms. Specific receptor proteins present in a growth cone allow it to recognize and respond to the appropriate guidance cues in its environment that direct it to its

correct target and establish the initial connectivity of the nervous system. See also: Immunoglobulin Gene Superfamily; Neurogenetics in Caenorhabditis elegans; Neurogenetics in Drosophila

Neuronal Specification R Baumeister Copyright ß 2001 Academic Press doi: 10.1006/rwgn.2001.0894

The nervous systems of both invertebrates and vertebrates are composed of a large variety of distinct cell types. The specification of cell fate results in the generation of the various types of neurons and determines their distinct structures, interconnectivity, neurotransmitters, surface receptors and other features characteristic for their individual function.

The Analysis of Gene Mutants Facilitates our Understanding of Neuronal Specification Mutations that significantly disturb the development of the nervous system reveal that this program is predominantly genetically determined. The characterization of mutants has allowed researchers to analyze and dissect the various steps required for the generation and differentiation of a neuron. Therefore, the mechanisms of neuronal specification are preferably studied in model organisms in which the following two prerequisites are fulfilled: 1. mutants can be isolated and characterized easily; 2. the fate of particular cells or cell groups can be followed during development. There are just a few organisms which are accessible to genetic and cellular analysis, among them the vertebrate models zebrafish (Brachydanio rerio) and mouse (Mus musculus). Currently the best characterized cell-fate decisions, however, have been described in invertebrates. These include the generation of mechanoreceptor cells in the nematode Caenorhabditis elegans and bristle hair and eye development in the fruitfly Drosophila melanogaster.

Neurogenesis Functions in a Hierarchical Manner A progressive determination model that accounts for the formation of various sensory organs during