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First published online 11 October 2006
doi: 10.1242/dev.02592

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Frizzled/RYK mediated signalling in axon guidance

Departamento de Neurobiología del Desarrollo, Instituto Cajal, CSIC, Dr Arce 37, Madrid 28002, Spain.

View larger version (62K): [in a new window]   Fig. 1. The three Wnt signalling pathways and their main components. (A) The canonical ß-catenin pathway is initiated by Wnt binding to Fz/Lrp, which activates Dvl, preventing ß-catenin phosphorylation through the Apc-Axin-Gsk3ß complex. ß-Catenin accumulates in the cytoplasm and translocates to the nucleus, where it activates transcription in association with Tcf. Downstream of Gsk3ß, a divergent pathway controls Map1B phosphorylation. The proposed Wnt-Ryk-Fz complex may function through the same pathway. (B) In the planar cell polarity (PCP) pathway, the binding of Wnt to Fz activates Dvl, which then signals either through Daam1, activating the small Rho GTPase, or through the small Rac GTPase, which in turn leads to JNK activation. Both GTPases then induce changes in the cytoskeleton. (C) In the the Wnt/calcium pathway, Wnt-Fz binding triggers PLC activation, which then hydrolyzes PIP2, generating IP3 and DAG. IP3 leads to the release of intracellular calcium, which activates the calcium/calmodulin dependent protein kinase II (CamKII) and PKC.,ß,, G-protein subunits; Apc, adenomatous polyposis coli; CamKII, calcium/calmodulin-dependent protein kinase II; Daam1, dishevelled associated activator of morphogenesis 1; DAG, diacylglycerol; Dvl, dishevelled; Fz, Frizzled receptor; Gsk3ß, glycogen synthetase kinase 3; IP3, inositol 1,4,5-trisphosphate receptor; JNK, jun kinase; Lrp, low-density lipoprotein receptor-related protein; Map1B, microtubule-associated protein 1B; NF-AT, nuclear factor of activated T cells; PIP2, phosphatidylinositol-4,5-bisphosphate; PKC, protein kinase C; PLC, phospholipase C; Rok, Rho kinase; Ryk, receptor-like tyrosine kinase; Tcf, T-cell factor.

View larger version (30K): [in a new window]   Fig. 2. Wnt-Drl/Ryk mediates axon repulsion in the Drosophila nerve cord and vertebrate cortico-spinal tract. (A-C) Schematics of a Drosophila nerve cord (NC) segment, illustrating anterior (ac) and posterior (pc) commissures. The axons of anterior commissural neurons (ACN) express derailed (drl; shown in blue) and are repelled by Wnt5 derived from midline cells (red circles). (A) In wild-type Drosophila, axons of posterior commissural neurons (PCN) do not express drl and enter the pc. (B) The misexpression of drl in PCN forces their axons through the ac. (C) Wnt5 loss of function (grey circles) suppresses the phenotype induced by drl ectopic expression, demonstrating that Wnt5, through Drl, is an essential cue for proper commissural axon projection. (D) Schematic of the cortico-spinal tracts (cst) in the dorsal portion of the postnatal mouse spinal cord. In vertebrates, a Ryk-mediated repulsive gradient of Wnt proteins (Wnt1 or Wnt5a) guides cortico-spinal axons in the AP direction. (E) Injections of anti-Ryk antibodies into the cervical spinal cord stall cortico-spinal axons posterior to the site of injection, with a consequent shortening of the cst. D, dorsal; V, ventral.

View larger version (18K): [in a new window]   Fig. 3. Wnt-Fz interaction mediates the rostral growth of post-crossing commissural axons in the vertebrate spinal cord. (A-C) Schematics of the vertebrate embryonic spinal cord in the open book configuration under (A) normal or (B,C) experimental conditions. (A) Commissural growth cones turn rostrally after crossing the midline, attracted by Wnt4 expressed in the floor plate in an anterior-high to posterior-low gradient (graded grey shading). (B) The addition of Wnt4-expressing cells at the caudal end of short spinal cord explants cultured in the open book configuration disrupts the Wnt gradient at the floor plate (solid blue colour) and reorients the axons toward the posterior spinal cord. (C) The addition of cells transfected with the Wnt inhibitor Sfrp2 in the proximity of the floor plate inactivates Wnt function (pale blue), and commissural axons stall at the floor plate or turn randomly. C, caudal; D, dorsal; FP, floor plate; R, rostral; V, ventral.

View larger version (31K): [in a new window]   Fig. 4. The retinotopic organisation of retinal projections requires Wnt activity in both vertebrates and invertebrates. (A) Schematic of the chick retinotectal projections under normal (left) or experimental conditions (right). In the chick, ventral retinal axons expressing both Ryk and Fz (red) project to the medial tectum, whereas dorsal axons expressing only Fz (blue) terminate in the lateral tectum. This organisation is achieved in part through the graded medial-high distribution (graded blue staining) of Wnt3a. Fz-positive dorsal retinal cell axons are attracted by low doses of Wnt3a. Misexpression of a dominant-negative (DN)-Ryk form in the dorsal RGCs (green staining) induces a medial shift of their terminal arborisations. (B) Schematic of the Drosophila visual system. Photoreceptor cells differentiate behind the morphogenetic furrow (mf) and project in an organised manner to the lamina after crossing though the optic stalk: ventral axons expressing Dfz2 (orange) are attracted by Dwnt4 (yellow) expressed in the ventral lamina. Iro expression (red) in the dorsal retina attenuates the competence of Dfz2-positive dorsal photoreceptors (grey) to respond to Dwnt4. Ectopic expression of Dwnt4 in the dorsal lamina attracts ventral axons to the dorsal lamina.

View larger version (15K): [in a new window]   Fig. 5. Wnt-Fz signalling controls anterior-directed projections of mechanosensory neurons in C. elegans. (A) In the 2-fold stage C. elegans embryo, egl-20(wnt) is expressed (red shading) in the tail behind anterior (AVM) and posterior (PVM) ventral mechanosensory neurons. (B) The position and projections of the different mechanosensory neurons of the worm (only one of the ALM and PLM bilateral pairs is shown; PVM and AVM are positioned on opposite hemi-sides of the embryo). (C) In double Wnt (cwn-1;egl-20)mutants or double Fz (mig-1; mom-5) mutants, the anterior projection of the AVM and PVM axons is impaired. Similarly, ALM axons do not branch in the nerve ring.

View larger version (38K): [in a new window]   Fig. 6. Hypothetical pathways that might link Wnt signalling to changes in the cytoskeletal organisation of the growth cone. Components typical of the non-canonical PCP pathway are represented in dark green, the classical or divergent canonical pathway in light blue, and the Ca2+ pathway in purple. General modulators of `classical' guidance cues are represented in pink. This hypothetical link suggests that components of the PCP pathway could mainly regulate actin dynamics (green), whereas, independently of transcriptional activity, the canonical pathway could regulate microtubule dynamics through Gsk3ß. Apc may function to link microtubule and microfilament dynamics. Apc, adenomatous polyposis coli; ASEF, rac-specific guanine nucleotide exchange factor; Axin, axis inhibition protein; CamKII, calcium/calmodulin-dependent protein kinase II; Cdc42, cell division cycle 42; cGMP, cyclic guanosine monophosphate; CRMP, collapsin response mediator protein; Daam1, dishevelled associated activator of morphogenesis 1; DAG, diacylglycerol; Dvl, dishevelled; Eph, ephrin receptor; Fried, frizzled-8 associated multidomain protein; Fz, Frizzled receptor; G, G-protein; Gsk3ß, glycogen synthetase kinase 3; IP3, inositol 1,4,5-trisphosphate receptor; JNK, jun kinase; LIMK, LIM domain kinase; Map1B, microtubule-associated protein 1B; PDE, phosphodiesterase; PKC, protein kinase C; PLC, phosphatidylinositol-specific phospholipase C; Rac, GTPase activator; Rho, ras homolog; Rok, Rho kinase; Ryk, receptor-like tyrosine kinase; Tau, neurofibrillary tangle protein.