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• W2044866443 abstract "How the complexity of neuronal interconnections becomes established during development has intrigued biologists ever since the neuron in its many elaborate forms was recognized as the fundamental building block of the nervous system. Although recent years have witnessed remarkable progress in elucidating the mechanisms that guide axons to their targets and identifying a number of the molecules involved (10Tessier-Lavigne M. Goodman C.S Science. 1996; 274: 1123-1133Crossref PubMed Scopus (2689) Google Scholar), barely two decades ago there was little more than a plethora of hypotheses. One of the most appealing of these, put forward by Ramon y Cajal in the last century, is that axons are guided to their targets by gradients of specific, diffusible chemoattractants. This idea lay dormant until a series of experiments in the late seventies showed that intracranial injection of Nerve Growth Factor (NGF) causes extensive growth of sympathetic axons into the brain (6Menesini-Chen M.G. Chen J.S. Levi-Montalcini R Arch. Ital. Biol. 1978; 116: 53-84PubMed Google Scholar), and that sensory axons turn toward a source of NGF in culture (3Gundersen R.W. Barrett J.N Science. 1979; 206: 1079-1080Crossref PubMed Scopus (396) Google Scholar). Although these observations were widely interpreted as evidence that sympathetic and sensory axons are guided to their targets by gradients of target-derived NGF, the demonstration that NGF is not synthesized in the targets of these neurons until the arrival of the earliest axons (2Davies A.M. Bandtlow C. Heumann R. Korsching S. Rohrer H. Thoenen H Nature. 1987; 326: 353-358Crossref PubMed Scopus (446) Google Scholar) showed that target-derived NGF could not play a role in long-range axonal guidance during development. Rather, its site and timing of expression accorded with its well-recognized role in promoting and regulating neuronal survival. A major flaw in the proposal that gradients of NGF guide sensory and sympathetic axons to their targets was a lack of specificity. It was difficult to imagine how gradients of a single molecule could account for the multiple specific routes taken by different sets of sympathetic and sensory axons to reach their widely dispersed targets. These considerations prompted the search for target-derived attractants that act specifically on their innervating axons. The approach pioneered in the early 80s was to coculture explants of neuronal populations with appropriate and inappropriate (control) targets at the stage of development when axons are growing to their targets in vivo. The cocultures were set up in a collagen matrix, which holds the explants in place, stabilizes gradients of putative diffusible chemoattractants, and provides an environment through which axons can grow. Observations that seemed to fulfil the criteria expected of a specific, target-derived chemoattractant first came from experiments in which mouse trigeminal ganglia were cocultured with their cutaneous targets (4Lumsden A.G. Davies A.M Nature. 1983; 306: 786-788Crossref PubMed Scopus (299) Google Scholar). The maxillary and mandibular processes, which receive their sensory innervation from the trigeminal ganglion, elicited and attracted neurite outgrowth from trigeminal ganglia at the stage when trigeminal axons normally start growing to these targets in vivo, whereas cutaneous targets innervated by other sensory neurons (the adjoining hyoid process or the forelimb bud) neither elicited nor directed early trigeminal axons (see figure). The diffusible trigeminal attractant, coined Maxillary (Max) Factor, appeared to emanate from the target field epithelium, because when early trigeminal ganglia were cocultured with isolated maxillary epithelium and mesenchyme, the axons grew toward the epithelium in a small percentage of cases but never toward the mesenchyme (5Lumsden A.G. Davies A.M Nature. 1986; 323: 538-539Crossref PubMed Scopus (190) Google Scholar). The demonstration that the early target-directed growth was not affected by function-blocking antibodies to NGF showed that this activity was not due to this neurotrophin. Although the collagen gel coculture paradigm paved the way for the identification and cloning of the first bona fide diffusible axon guidance molecules, the netrins (8Serafini T. Kennedy T.E. Galko M.J. Mirzayan C. Jessell T.M. Tessier-Lavigne M Cell. 1994; 78: 409-424Abstract Full Text PDF PubMed Scopus (1161) Google Scholar, 11Tessier-Lavigne M. Placzek M. Lumsden A.G.S. Dodd J. Jessell M Nature. 1988; 336: 775-778Crossref PubMed Scopus (569) Google Scholar), the identity of Max Factor remained elusive. In this issue of Neuron, the identities of the molecules responsible for this in vitro activity have been pinned down by 7O'Connor R. Tessier-Lavigne M Neuron. 1999; 24 (this issue,): 165-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar. In a comprehensive set of carefully controlled experiments, they show that two neurotrophins that had not been cloned at the time when Max Factor activity was first identified—neurotrophin-3 (NT-3) and, to a lesser extent, Brain-Derived Neurotrophic Factor (BDNF)—can account for at least the neurite growth-promoting activity of the trigeminal target field on early trigeminal ganglion explants. The key findings were that target-stimulated neurite outgrowth in the early trigeminal coculture paradigm could be prevented by reagents that inhibit the activity of these neurotrophins. Anti-NT-3 antibodies and, to a lesser extent, anti-BDNF antibodies reduced neurite outgrowth, and both antibodies in combination completely eliminated it. Likewise, TrkC–Fc (which selectively blocks NT-3) markedly reduced neurite outgrowth, and TrkB–Fc (which blocks both NT-3 and BDNF) eliminated outgrowth. In addition, they showed that maxillary tissue from NT-3−/− embryos elicited very little outgrowth from early trigeminal ganglia compared with wild-type tissue and that maxillary tissue from BDNF−/− embryos had slightly reduced neurite outgrowth-promoting activity compared with wild-type tissue, confirming that NT-3 is the major and BDNF is the minor component of the growth-promoting activity of Max Factor. The demonstration that NT-3 and BDNF are essential components of Max Factor activity was at odds with the conclusion that this activity emanates from target field epithelium and not mesenchyme (5Lumsden A.G. Davies A.M Nature. 1986; 323: 538-539Crossref PubMed Scopus (190) Google Scholar), because previous studies have shown that NT-3 and BDNF are expressed predominantly in mesenchyme at the stage when trigeminal axons are growing to their targets (1Buchman V.L. Davies A.M Development. 1993; 118: 989-1001PubMed Google Scholar). However, 7O'Connor R. Tessier-Lavigne M Neuron. 1999; 24 (this issue,): 165-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar provided an explanation for this discrepancy in showing that the level of NT-3 decreases markedly in cultured mesenchyme when it is separated from epithelium. Earlier work had also showed that NT-3 and BDNF are expressed in the hyoid process (1Buchman V.L. Davies A.M Development. 1993; 118: 989-1001PubMed Google Scholar), which did not promote neurite outgrowth from early trigeminal ganglia (4Lumsden A.G. Davies A.M Nature. 1983; 306: 786-788Crossref PubMed Scopus (299) Google Scholar). Here again, 7O'Connor R. Tessier-Lavigne M Neuron. 1999; 24 (this issue,): 165-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar provided an explanation; in a detailed analysis of NT-3 mRNA expression by in situ hybridization, they found that NT-3 mRNA was much lower in the distal part of the hyoid process (which was used in the original coculture experiments) than in the proximal part. Although NT-3 and BDNF are necessary components of Max Factor activity, 7O'Connor R. Tessier-Lavigne M Neuron. 1999; 24 (this issue,): 165-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar showed that these neurotrophins are not required for directing the initial growth of trigeminal axons to their peripheral targets in vivo, because the gross pattern and growth of the trigeminal nerve appear normal in NT-3−/−;BDNF−/− embryos. As they point out, this does not exclude a possible involvement of neurotrophins (including NGF) at later stages—for example, in the potential chemoattraction of the fine maxillary nerve branches to the prospective whisker sensory epithelium. The results also leave open the question of what guides trigeminal axons along their initial trajectory. Could there yet be a specific target-derived chemoattractant in addition to neurotrophins, which could contribute to the attractive effect of the target observed in vitro (4Lumsden A.G. Davies A.M Nature. 1983; 306: 786-788Crossref PubMed Scopus (299) Google Scholar)? Chemoattraction per se could not be assayed in the absence of neurotrophins, which are required for the axons to grow out. Thus, as pointed out by the authors, the experiments do not exclude the existence of a chemoattractant that lacks outgrowth activity. A precedent for this possibility is actually provided by floor plate chemoattraction, which is known to be mediated by both netrin-1 and a second unidentified chemoattractant that lacks outgrowth-promoting activity (9Serafini T. Colamarino S. Leonardo D. Wang H. Beddington R. Skarnes W.C. Tessier-Lavigne M Cell. 1996; 87: 1001-1014Abstract Full Text Full Text PDF PubMed Scopus (1062) Google Scholar). Whether such an attractant exists in the trigeminal system remains to be determined. Whatever the mechanisms guiding trigeminal axons, however, 7O'Connor R. Tessier-Lavigne M Neuron. 1999; 24 (this issue,): 165-178Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar have provided a very plausible explanation for an in vitro observation that has influenced our thinking about axonal guidance and brought chemotropism to the fore as an important component of axon guidance." @default.
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