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• W2022674223 abstract "Following neurogenesis and the initial steps of axon pathfinding, growth cones approach their target cells and initiate the process of synapse formation. Much of our knowledge regarding the mechanisms that regulate synapse formation arises from studies of developing neuromuscular synapses. These studies suggest that presynaptic and postsynaptic cells exchange signals that stimulate and coordinate their mutual differentiation (2Burden S.J Genes Dev. 1998; 12: 133-148Crossref PubMed Scopus (166) Google Scholar). Although there are hints that similar paradigms, including reciprocal signaling, might regulate synapse formation in the central nervous system (CNS), the mechanisms that govern synapse formation in the CNS are poorly understood, and signaling molecules that regulate CNS synapse formation and differentiation have not been identified. In this issue of Cell, 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar now report that Wnts, signaling molecules that are known for their diverse and widespread roles during embryonic development, are synthesized by postsynaptic cerebellar granule cells (GCs) and remodel the axons and growth cones of presynaptic mossy fibers. Importantly, their findings indicate that Wnts can act as retrograde synaptogenic factors in the CNS. Wnt proteins are a large (>16 members) family of cysteine-rich, secreted signaling molecules, associated with the extracellular matrix, that regulate cell fate decisions, cell polarity, and embryonic patterning (14Parr B.A McMahon A.P Curr. Opin. Genet. Dev. 1994; 4: 523-528Crossref PubMed Scopus (157) Google Scholar, 18Wodarz A Nusse R Annu. Rev. Cell Dev. Biol. 1998; 14: 59-88Crossref PubMed Scopus (1668) Google Scholar, 4Eastman Q Grosschedl R Curr. Opin. Cell Biol. 1999; 11: 233-240Crossref PubMed Scopus (454) Google Scholar). Wnts bind to a similarly large family of seven pass transmembrane proteins, termed Frizzleds. Wnt-binding leads to inhibition of GSK3β, a serine/threonine kinase with multiple substrates, including β-catenin and several microtubule-associated proteins. Inhibition of GSK3β results in stabilization and accumulation of β-catenin, allowing β-catenin to associate with members of a family of four related HMG proteins, LEF-1/TCFs, that activate transcription of Wnt target genes. Pharmacological inhibition of GSK3β leads to decreased phosphorylation of microtubule-associated proteins, resulting in destabilization and unbundling of microtubules, leading to changes in cell shape. 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar investigated Wnt function in the developing cerebellar cortex. The cerebellar cortex is a stratified structure containing five classes of neurons, organized in two distinct cellular layers. GCs, which occupy the innermost layer, are by far the most numerous type of cerebellar neuron, and they receive synaptic input from mossy fibers originating in vestibular and somatosensory centers and in the pontine nucleus of the brain stem (Figure 1). Because of its relatively simple anatomical organization, the ability to study cell migration and synapse formation in vitro and the availability of naturally occurring mouse mutants with defects in cerebellar differentiation, the cerebellum has been a favored system for studying neural development. GC precursors begin to migrate from the external to internal granular layer approximately 1 week after birth in the mouse. Mossy fiber axons, waiting in the internal granular layer, begin to form synaptic contacts with GC neurons during the following week. Mossy fiber/GC synapses are located in glomerular rosettes, which are formed by elaborate expansions of a mossy fiber nerve terminal embedded within the dendrites of numerous granule cells (Figure 1). The signals that guide mossy fiber axons to the cerebellum are not known, but the mossy fiber growth cones enlarge and become multilobulated as mossy fiber axons approach and intermingle with GC dendrites, suggesting that an exchange of signals between mossy fibers and GCs regulates their differentiation. Indeed, studies of mouse mutants lacking GCs indicate that GCs are required for glomerular formation (17Sotelo C Brain Res. 1975; 94: 19-44Crossref PubMed Scopus (213) Google Scholar), and cell culture experiments indicate that GCs provide cell surface-associated “stop” signals that arrest the growth of mossy fiber axons (1Baird D.H Hatten M.E Mason C.A J. Neurosci. 1992; 12: 619-634PubMed Google Scholar, 20Zhang Q Mason C.A Dev. Biol. 1998; 195: 75-87Crossref PubMed Scopus (15) Google Scholar). 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar show that cultured GC neurons secrete factors that alter the morphology of mossy fiber axons and growth cones. GC-conditioned medium increases the diameter of mossy fiber axons, induces axonal spreading and branching, and promotes axon fasciculation. In addition, GC-conditioned medium increases the size and complexity of mossy fiber growth cones—a shape change that resembles the multilobulated appearance of mossy fiber terminals seen in vivo. Hall et al. find that Wnt-7a, which is expressed by GC neurons, can mimic most of the effects of GC-conditioned medium as well as increase synapsin I-staining in the remodeled axons. GC-conditioned medium, however, increases growth cone complexity more than Wnt-7a, raising the possibility that additional factors in GC-conditioned medium regulate the remodeling of growth cones. Importantly, the effects of GC-conditioned medium that are mimicked by Wnt-7a can be blocked by a soluble, dominant interfering form of Frizzled. Taken together, these data support the idea that much of the axon and growth cone remodeling activity of GC-conditioned medium is attributable to Wnt-dependent signaling. Consistent with the proposed role for Wnt-7a inferred from these in vitro experiments, 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar report that transient defects in mossy fiber presynaptic differentiation can be detected in Wnt-7a mutant mice. Hall et al. visualized glomerular rosettes by staining for synapsin I, present in mossy fiber axons, and found that the size of synapsin I-stained areas are reduced in Wnt-7a mutants. This reduction is small and transient—detectable at P8 and P10 but not thereafter. Electron microscopic studies show that mossy fiber endings are less convoluted in Wnt-7a mutant mice than in wild-type mice, indicating that differentiation of mossy fiber axons is delayed in these mutants. The expression of multiple Wnts in the cerebellum (11McMahon A.P Bradley A Cell. 1990; 62: 1073-1085Abstract Full Text PDF PubMed Scopus (1204) Google Scholar, 15Salinas P.C Fletcher C Copeland N.G Jenkins N.A Nusse R Development. 1994; 120: 1277-1286PubMed Google Scholar, 8Lucas F.R Salinas P.C Dev. Biol. 1997; 192: 31-44Crossref PubMed Scopus (234) Google Scholar) and the redundant roles of Wnts in other tissues raise the possibility that other Wnts compensate for the loss of Wnt-7a and provide a potential explanation for the weak phenotype. Alternatively, Wnts may cooperate with other signaling molecules, such as Shh, which synergizes with Wnts to regulate myogenesis (12Munsterberg A.E Kitajewski J Bumcrot D.A McMahon A.P Lassar A.B Genes Dev. 1995; 9: 2911-2922Crossref PubMed Scopus (432) Google Scholar). Future studies, following upon the new and exciting findings described by 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar, will seek to establish more firmly a role for Wnt signaling in vivo—perhaps by expressing a dominant-negative form of Frizzled in mossy fibers to interfere with potential signaling by multiple Wnts and to elicit a more potent and persistent effect on synapse formation. Likewise, it will be interesting to block Wnt signaling in mossy fiber/GC cocultures, using dominant-negative forms of Frizzled, to learn whether Wnt signaling primes or is required for synapse formation between mossy fibers and GCs. It is interesting that GCs, cultured from mice prior to innervation in vivo, release factors that remodel mossy fiber axons and growth cones. Thus, it appears that these factors are expressed constitutively and are not induced by innervation. Nevertheless, it is possible that innervation has a role in localizing the remodeling activity to dendrites, where it may enhance synaptic differentiation more effectively. In this regard, although the remodeling activities are soluble in cell culture, it is possible that these signals are associated with the extracellular matrix in vivo, as one might expect for Wnts; thus, their spatial range of influence may be substantially less in vivo than in cell culture. Mossy fibers are not the only input to GCs, since Golgi cells, within the cerebellar cortex, also innervate GCs. Since the terminals of Golgi cells terminate on GC dendrites, adjacent to mossy fiber terminals in glomerular rosettes, Golgi cell axons and growth cones may also be sensitive to Wnt signaling. Likewise, since mossy fibers also innervate Golgi cells, it is natural to wonder whether Golgi cells also provide Wnts to incoming mossy fibers. Furthermore, since GCs are themselves responsive to Wnts (8Lucas F.R Salinas P.C Dev. Biol. 1997; 192: 31-44Crossref PubMed Scopus (234) Google Scholar), it is possible that autocrine signaling might have a role in regulating GC differentiation and the elaboration of GC dendrites. The persistent expression of Wnts in the adult nervous system raises the possibility that Wnt signaling has an important role in synaptic plasticity in addition to its well-established role in patterning the early nervous system. Indeed, Wnts act focally to regulate changes in cell shape, and changes in the shape of presynaptic terminals and postsynaptic spines are thought to underlie changes in synaptic function and possibly learning (5Engert F Bonhoeffer T Nature. 1999; 399: 66-70Crossref PubMed Scopus (1314) Google Scholar, 9Maletic-Savatic M Malinow R Svoboda K Science. 1999; 283: 1923-1927Crossref PubMed Scopus (972) Google Scholar). Thus, Wnts would appear to be particularly well suited as mediators of synaptic plasticity. Wnt signaling can alter cell behavior by transcriptional and posttranslational mechanisms. 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar provide evidence that Wnt-7a unbundles microtubules in mossy fiber axons, an effect that is mimicked by lithium inhibition of Gsk3β, suggesting that such destabilization is an early step in growth cone initiation. These results also raise the possibility that the effectiveness of lithium as a therapeutic agent for bipolar disorders might be dependent upon lithium inhibition of Wnt signaling in the CNS (7Klein P.S Melton D.A Proc. Natl. Acad. Sci. USA. 1996; 93: 8455-8459Crossref PubMed Scopus (1995) Google Scholar). Hall et al. also show that Wnt-7a increases synapsin I staining in axons, a change that could be attributed to changes in expression and/or distribution of synapsin I. A large family of Cadherins and Cadherin-related proteins, which are expressed in the CNS, have been postulated to regulate synapse formation and plasticity (13Murase S Schuman E.M Curr. Opin. Cell Biol. 1999; 11: 549-553Crossref PubMed Scopus (146) Google Scholar, 16Serafini T Cell. 1999; 98: 133-136Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar). Although Wnt signaling is not currently thought to regulate Cadherin-mediated adhesion, the synapse is a new context for Wnt signaling; thus, it will be interesting to learn whether Wnt signaling remodels growth cones and synapses by regulating the function of these adhesion molecules. It is natural to wonder whether Wnt signaling has a role in regulating neuromuscular synapse formation. The formation of neuromuscular synapses depends upon agrin signaling. Agrin is a ∼200 kDa protein synthesized by motor neurons, transported in motor axons, and deposited into the extracellular matrix that separates the motor nerve terminal from the muscle postsynaptic membrane. Agrin activates MuSK, a muscle-specific receptor tyrosine kinase, and MuSK activation triggers multiple aspects of postsynaptic differentiation. Genetic evidence supports the idea that MuSK activation also stimulates the production and/or clustering of a muscle-derived signal that acts in a retrograde manner to stop motor axon growth and to induce differentiation of presynaptic motor axon terminals (2Burden S.J Genes Dev. 1998; 12: 133-148Crossref PubMed Scopus (166) Google Scholar). This retrograde signal(s) has not been identified. Perhaps Wnts should be added to the list of candidate molecules? In this regard, it is interesting that the cysteine-rich domain in Frizzled is related to the cysteine-rich domain in MuSK (10Masiakowski P Yancopoulos G.D Curr. Biol. 1998; 8: R407Abstract Full Text Full Text PDF PubMed Google Scholar, 19Xu Y.K Nusse R Curr. Biol. 1998; 8: R405-R406Abstract Full Text Full Text PDF PubMed Google Scholar), raising the possibility that MuSK might bind and present Wnts to motor axons as they contact muscle cells, release agrin, and initiate postsynaptic differentiation. Alternatively, Wnts could function at an earlier stage in neuromuscular synapse formation. Following pathfinding of motor axons to developing limbs, motor axons undergo a waiting period before invading the limb muscle; the resumption of motor axon growth is thought to depend upon signals provided by developing myotubes (3Dahm L.M Landmesser L.T Dev. Biol. 1988; 130: 621-644Crossref PubMed Scopus (135) Google Scholar). Perhaps, analogous to the proposed role for Wnts in remodeling mossy fiber growth cones in the cerebellum, Wnts might act to stimulate motor axon growth following this waiting period. 6Hall A.C Lucas F.R Salinas P.C Cell. 2000; 100: 525-535Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar have shown that Wnt-7a, synthesized by postsynaptic GCs, can regulate the structure of presynaptic mossy fiber axons and growth cones in cell culture. The authors present convincing but less striking evidence that Wnts have a role in remodeling axons and growth cones in vivo. The multiplicity of Wnts, Frizzleds, and transcription factors activated by Wnt signaling presents a daunting challenge for those seeking to decipher the precise roles of Wnt signaling in vivo. Nevertheless, such complexity would appear appropriate for regulating the structure and function of synapses in the CNS." @default.
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• W2022674223 title "Wnts as Retrograde Signals for Axon and Growth Cone Differentiation" @default.
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• W2022674223 cites W2004191360 @default.
• W2022674223 cites W2013317069 @default.
• W2022674223 cites W2026649263 @default.
• W2022674223 cites W2032649512 @default.
• W2022674223 cites W2040448753 @default.
• W2022674223 cites W2047982560 @default.
• W2022674223 cites W2051788298 @default.
• W2022674223 cites W2052459095 @default.
• W2022674223 cites W2058073823 @default.
• W2022674223 cites W2064117255 @default.
• W2022674223 cites W2067594083 @default.
• W2022674223 cites W2073297965 @default.
• W2022674223 cites W2090449445 @default.
• W2022674223 cites W2165061154 @default.
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