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First published online 21 December 2006
doi: 10.1242/dev.02762

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Getting axons onto the right path: the role of transcription factors in axon guidance

¹ Department of Biological Sciences, HNB 201, 3641 Watt Way, University of Southern California, Los Angeles, CA 90089, USA.
² MRC Centre for Developmental Neurobiology, New Hunts House, Guys Campus, Kings College, London SE1 1UL, UK.

View larger version (24K): [in this window] [in a new window]   Fig. 1. General mechanisms of axon guidance. The response of a growth cone to signals in the environment depends on the complement of receptors it expresses. (A) The growth cone will be unresponsive to external guidance cues if it does not contain the relevant receptors to perceive a gradient of either a chemoattractant (red) or of a chemorepellent (blue). (B) If the growth cone expresses the appropriate chemorepellent receptor (light blue), the activation of this receptor will result in the local depolymerisation of the actin cytoskeleton, such that the growth cone reorients away from the repellent. (C) Alternatively, activation of a chemoattractant receptor (red) in the growth cone results in the stabilization and extension of filopodia, such that the growth cone extends towards the attractant. Schematic of growth cone modified with permission from Forscher and Smith (Forscher and Smith, 1988).

View larger version (36K): [in this window] [in a new window]   Fig. 2. Combinatorial action of LIM-homeodomain and Hox transcription factors dictate Drosophila and vertebrate motor axon guidance. Motor neurons (MNs) in Drosophila and vertebrates can be identified by the routes that they take and the muscle fields that they innervate. (A) In Drosophila, most MNs exit from the ventral nerve cord along two major nerve routes, the segmental nerve (SN) and intersegmental nerve (ISN), from which they defasciculate to innervate discreet populations of muscles (represented by numbers 1-29). The MNs express different combinations of transcription factors that appear to dictate which muscle fields they innervate, as shown in the key. (B) In vertebrate spinal cord, somatic MNs are arranged in columns that project to common targets and can be distinguished by the combinatorial expression of LIM-homeodomain transcription factors (see key). The medial motor column (MMC; blue) projects axons to axial muscle, whereas, at the brachial and lumbar levels, the lateral motor column (LMC; red and green) projects to the limb. On reaching the limb, the LMC subdivides such that the medial (m) division (red) projects to the ventral limb, whereas the lateral (l) division (green) projects to the Scapulohumeralis (Sca) muscle of the dorsal limb. These divisions are further subdivided into pools of MNs that innervate particular muscle groups. At brachial levels, the LMC is subdivided by the expression of Hox5 and Hoxc8, which appear to control the projection pattern of LMC axons into distinct motor pools in the Pec (pectoralis), anterior latimuss dorsi (ALD) and flexor carpi ulnaris (FCU) muscles. (A) Modified with permission from Landgraf and Thor (Landgraf and Thor, 2006) and (B) modified with permission from Kania et al. (Kania et al., 2000).

View larger version (31K): [in this window] [in a new window]   Fig. 3. Retinotectal axon guidance requires the graded expression of receptors and ligands, as well as a possible paracrine role for a transcription factor. (A) Retinal ganglion cells (RGCs) project axons in an orderly manner from the retina to the tectum in order to ensure that an image (red arrow) perceived in the retina is precisely represented in the tectum. Axons from the temporal (T) region of the retina project to the anterior (A) region of the tectum, whereas axons from the nasal (N) region extend to posterior (P) tectum. Formation of this precise retinotopic map relies on the graded activity of several molecules, including the EphA receptor tyrosine kinases, their ephrin ligands and the transcription factor En-2. RGCs with high EphA-receptor levels are repelled by ephrin and navigate to the tectal region that has lower levels of the ligand. RGCs with lower receptor levels can extend into regions of the tectum with higher levels of ephrin. En-2 levels in the tectum also influence map formation, with temporal axons avoiding posterior regions of the tectum that have higher levels of En-2. (B) En-2 can act as a soluble molecule to differentially influence the outgrowth of temporal and nasal RGCs. In an in vitro turning assay, nasal axons are attracted to a source of En-2(+), whereas temporal axons are repelled by high levels of En-2. (C) En-2 enters the temporal and nasal growth cones where it stimulates eIF4E and eIF4E-BP phosphorylation. Phosphorylated eIF4E is believed to trigger the translation of different proteins in nasal and temporal axons to generate an attractive or repulsive response, respectively.

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