Articles

The Molecular Biology of Axon Guidance

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Science  15 Nov 1996:
Vol. 274, Issue 5290, pp. 1123-1133
DOI: 10.1126/science.274.5290.1123

Figures

  • Fig. 1.

    Guidance forces. Four types of mechanisms contribute to guiding growth cones: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. The term attraction is used here to refer to a range of permissive and attractive effects, and the term repulsion to a range of inhibitory and repulsive effects (8). Examples are provided of ligands implicated in mediating each of these mechanisms. There is not a one-to-one match between molecules and mechanisms because some guidance molecules are not exclusively attractive or repulsive, but rather bifunctional, and some families of guidance cues have both diffusible and nondiffusible members. Individual growth cones might be “pushed” from behind by a chemorepellent (red), “pulled” from afar by a chemoattractant (green), and “hemmed in” by attractive (gray) and repulsive (yellow) local cues. Axons can also be guided by cues provided by other axons (selective fasciculation). Push, pull, and hem: these forces act together to ensure accurate guidance.

  • Fig. 2.

    Molecules that modulate axon growth. (A) Representatives of various subfamilies of the immunoglobulin (Ig) superfamily, including receptor protein tyrosine kinases (RPTKs) and receptor protein tyrosine phosphatases (RPTPs), that have been implicated as ligands or receptors (or both) in axon guidance (names shown are for those mentioned in the text). Some members of the Ig superfamily have extracellular domains possessing only tandem Ig domains, whereas others have both tandem Ig and fibronectin type III (FNIII) domains, or yet other motifs. For certain subfamilies, the first members were identified as proteins expressed on subsets of axons in the developing nervous system. For other subfamilies, the first members were identified in functional screens for adhesion molecules (CAMs). Yet other members (for example, UNC-40 and UNC-5) were identified as putative guidance receptors (the latter have longer cytoplasmic domains than CAMs). Some Ig superfamily members are linked to cell membranes by a GPI anchor. Many RPTKs and RPTPs implicated in axon guidance also have extracellular domains comprising tandem Ig domains or FNIII domains, or both. These subfamilies are highly conserved among vertebrates, insects, and nematodes. Ig, immunoglobulin domain; FNIII, fibronectin type III domain; TSI, thrombospondin type I domain; CR, cysteine-rich region; PTK, protein tyrosine kinase domain; PTP, protein tyrosine phosphatase domain. (B and C) The laminin, netrin, and semaphorin families of guidance molecules are conserved in structure and apparently in function among nematodes, insects, and vertebrates. (B) The laminins are heterotrimeric, cruciform glycoprotein complexes with constituent chains called α, β, and γ. There are at least five α, three β, and two γ chains in vertebrates. The netrins are related to the amino-terminal domains VI and V of laminin chains, although they then diverge from laminin sequences and are much shorter. (C) The semaphorins are a large family of cell-surface and secreted proteins. Most semaphorins are ∼750 amino acids in length and share a common ∼500-amino acid semaphorin domain; in several of these subfamilies, the semaphorin domain is followed by an Ig domain. One subfamily, however, contains members that are over 1000 amino acids in length; in these proteins, the semaphorin domain is followed by a set of tandem thrombospondin type I domains.

  • Fig. 3.

    Long-range and short-range guidance at the ventral midline. A composite picture of guidance at the midline drawing on mechanisms identified in nematodes, fruit flies, and vertebrates, at least some of which (and possibly all of which) are conserved among these organisms. The netrins appear to function as both long-range chemoattractants (green) and chemorepellents (red) for distinct classes of axons. Attraction of growth cones by netrins involves the DCC/UNC-40/Frazzled receptor (as shown in all three phyla), whereas repulsion of growth cones by netrins involves the UNC-5 receptor (as shown in C. elegans). In chick, crossing of the midline requires interaction of the Ig CAM axonin-1/TAG-1 on commissural axons with NrCAM on the surface of midline cells. In Drosophila, it also requires the midline expression of Commissureless (the growth cone receptor for Comm is at present unknown). Many commissural growth cones turn longitudinally along the midline after crossing. In Drosophila, the phenotype of robo mutants, when coupled with recent molecular data (93), is consistent with the hypothesis that axons express the putative Robo receptor that appears to function as a repulsive receptor for an unknown contact-mediated repellent at the midline, thus preventing these growth cones from recrossing the midline.

  • Fig. 4.

    Molecules that mediate fasciculation and defasciculation. (A and B) Axonal fasciculation appears to depend on a balance of attraction and repulsion. Ig CAMs such as Fasciclin II or L1/NgCAM on subsets of axons can function to “pull” axons together. Recent experiments also suggest that repulsive signals (possibly Eph ligands or transmembrane semaphorins) on surrounding cells or other subsets of axons can create an inhibitory environment that “pushes” axons together. (C and D) Mechanisms that regulate defasciculation. (C) Polysialic acid can drive the defasciculation of motor axons in the chick embryo, apparently by interfering with axon-axon adhesion mediated by the Ig CAM L1/NgCAM. (D) In Drosophila, defasciculation of SNb motor axons from the major motor nerve (ISN) at a specific choice point involves the modulation of Fasciclin II function by several RPTPs, as well as by the secreted protein Beat. Fig. 5. Target recognition involves selection of target region, topographic location, and discrete termination site. The steps involved in finding an appropriate target are illustrated for the projection of retinal ganglion cells to the optic tectum in the chick embryo. (A) Growth cones recognize and invade specific target regions. (B) Within a target region, like the optic tectum, growth cones may be guided to their topographically appropriate termination sites by gradients of guidance cues. Thus, axons from nasal (N) retina project to posterior (P) tectum, and from temporal (T) retina to anterior (A) tectum. In the chick tectum, Eph ligands function as repellents for retinal axons and are expressed in gradients on the tectum. ELF-1 is expressed in an increasing anterior-to-posterior gradient across the entire tectum, and RAGS in a similar gradient across the posterior portion of the tectum. The Eph receptor Mek-4, which binds to both ELF-1 and RAGS, is expressed in a reciprocal gradient across the retina, with highest expression in the temporal retina. (C) Growth cones are also able to select discrete targets. In the chick embryo, retinal growth cones select a specific laminar termination site from among 16 laminae.

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