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First published online April 27, 2005
doi: 10.1242/10.1242/dev.01830

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Novel brain wiring functions for classical morphogens: a role as graded positional cues in axon guidance

Frédéric Charron^1,* and Marc Tessier-Lavigne^1,2,

¹ Department of Biological Sciences, Stanford University, 371 Serra Mall, Stanford, California 94305, USA
² Genentech Incorporated, 1 DNA Way, South San Francisco, California 94080, USA

View larger version (32K): [in a new window]   Fig. 1. Neuronal cell fate specification and guidance of commissural axons by morphogens and Netrin 1. Three sets of morphogens, Shh, BMPs and Wnts, are first used to pattern neural progenitors in the spinal cord, and then appear to be reused as guidance cues for commissural axons. (A) In the early neural tube, Shh, BMP and Wnt protein concentration gradients act to specify neural cell fate in the ventral and dorsal spinal cord. (B) Later, the axons of differentiated commissural neurons are repelled from the dorsal midline by BMPs (red) and attracted to the ventral midline by the combined chemoattractant effects of Netrin 1 and Shh (blue). (C,D) After crossing the floor plate, commissural axons are attracted anteriorly by a Wnt4 gradient (C, green) and repelled from the posterior pole by a Shh gradient (D, orange). A and B, and left panels in C and D, are cross section representations of the developing spinal cord; right panels in C and D are open book representations. V0-3, ventral interneuron sub-populations; dI1-6, dorsal interneuron sub-populations; MN, motoneurons; RP, roof plate; FP, floor plate; D, dorsal; V, ventral; P, posterior; A, anterior.

View larger version (28K): [in a new window]   Fig. 2. Overview of the Shh, TGFß/BMP and Wnt morphogenic signaling pathways. (A) Shh signaling pathway. Genetic and biochemical experiments have shown that Hhs activate signaling by binding to their receptor Patched (Ptc; a 12-pass transmembrane protein), which leads to the relief of Ptc-mediated inhibition of Smoothened (Smo), a seven-pass transmembrane (7TM) protein, which can then activate downstream signaling. Smo associates directly with a Ci-containing complex, which contains the atypical kinesin Costal 2 (Cos2), the protein kinase Fused (Fu) and the Suppressor of Fused [Su(fu)]. This complex constitutively suppresses pathway activity by leading to the proteolytic cleavage of Ci, which acts as a transcriptional repressor. Activation of Hh signaling reverses this regulatory effect and leads to the production of full-length Ci, which activates transcription of Hh target genes. (B) TGFß/BMP signaling pathway. Members of the Dpp/BMP/TGFß family regulate cell fate by inducing the dimerization of type I and type II TGFß receptors, resulting in phosphorylation and activation of the intracellular kinase domain of the type I receptor. Targets of the type I receptor are the receptor-regulated Smads (R-Smads) which, upon phosphorylation, associate with co-Smads and translocate to the nucleus where, together with DNA-binding partners such as Fast1, they activate transcription. (C) Wnt signaling pathway. Wnt ligands can activate several different signal transduction pathways. The canonical Wnt pathway controls gene expression by stabilizing ß-Catenin (ß-Cat). Frizzled (Fz) proteins are 7TM molecules that together with the low-density lipoprotein (LDL) receptor-related protein 5 and 6 (LRP5/6; Arrow in Drosophila) family of co-receptors, function as Wnt receptors. When Wnts are absent, ß-Catenin is phosphorylated by GSK3ß, leading to its proteasomal degradation. This process requires the formation of a complex scaffolded by Axin and adenomatous polyposis coli (Apc). Binding of Wnts to their receptors results in Dishevelled (Dsh) activation and suppression of GSK3ß activity, thus protecting ß-Catenin from degradation. Accumulated ß-Catenin converts the lymphoid enhancer factor (Lef)/Tcf from a transcriptional repressor to an activator. Two non-canonical Wnt pathways are: the Wnt/Ca2+ pathway and the planar cell polarity (PCP) pathway. The PCP pathway involves a non-canonical, ß-Catenin-independent, Wnt/Fz pathway that requires Dsh. A Wnt ligand for this pathway has yet to be identified in Drosophila, but Wnt ligands can activate an analogous pathway in vertebrates. The Wnt/Ca2+ pathway probably signals via heterotrimeric G-proteins (, ß and subunits) to mobilize intracellular Ca2+ and, in some contexts, to stimulate protein kinase C (PKC). In vertebrates, Wnt/Ca2+ signaling is activated by the same ligands as the PCP pathway, suggesting that these pathways might overlap.

View larger version (22K): [in a new window]   Fig. 3. Shh expression at the chiasm border defines a barrier within the ventral midline that is implicated in guiding RGC axons. Retinal ganglion cell (RGC) axons growing towards the diencephalic ventral midline project either contralaterally or ipsilaterally in response to guidance cues at the optic chiasm. (A) In wild-type animals, downregulation of Shh expression allows RGC axon decussation and formation of the chiasm. (B) Ectopic expression of Shh in the ventral midline region interferes with RGC axon growth and prevents them from crossing the midline. The Shh expression domain is shown in blue. Shh can inhibit retinal axons in vitro, suggesting that in vivo it might act on axons directly rather than by altering the expression of distinct guidance cues in the chiasm, although conclusive evidence for this guidance function in vivo remains to be obtained. A, anterior; P, posterior; POA, pre-optic area; VH, ventral hypothalamus.

View larger version (23K): [in a new window]   Fig. 4. Wnt5 repels commissural axons from the posterior commissure. During Drosophila development, the axons composing the CNS have a ladder-like structure: each segment comprises an anterior and a posterior commissural tract that cross the midline and join the longitudinal tracts. (A) In wild-type animals, the Wnt5 ligand, which is restricted to the posterior commissure (red), repels axons expressing Derailed (Drl+; light green) from the posterior commissure into the anterior commissure. (B) In wnt5 mutants (as well as in drl mutants, not shown), the Drl+ neurons that normally project into the anterior commissure project into the posterior commissure. A, anterior; P, posterior.