Neurotrophic factors in action – new dogs and new tricks

摘要: The possibility of an independent signalling capacity GDNF Rα raises old quandary, namely the physiological role p75, low-affinity NGF receptor (for review, see Refs 9xChao, M.V. J Neurobiol. 1994; 25: 1373–1385Crossref | PubMed Scopus (343)See all ReferencesRefs 9,10xGreene, L.A. and Kaplan, D.R. Curr Opin 1995; 5: 579–587Crossref (261)See References10). Progress in this field was also reported at meeting. There is mounting evidence to suggest that p75 a capable signalling, although neurotrophins following binding still quite controversial. In some cells, overexpression absence TrkA has been found induce apoptosis via ceramide pathway can be quenched by (Ref. 11xDobrowsky, R.T. et al. Science. 265: 1596–1599Crossref PubMedSee ReferencesRef. 11). But Schwann cells activation promotes nuclear translocation factor kappa B (NFκB)12xCarter, B.D. 1996; 272: 542–545Crossref References12, characteristic feature stress induction. Careful examination target innervation SCG neurones knockout mouse shows complete loss pineal gland stochastic salivary which about 50% project13xLee, K.F. 263: 1447–1449Crossref References13. Thus, terms neuronal survival, consensus opinion modulate NGF, for example enhancing affinity 14xLee, K.F., Davies, A.M., Jaenisch, R. Development. 120: 1027–1033PubMedSee 14), but neither unligated or ligated play roles as mediators anti-apoptotic signals. Biochemical ‘presents’ indirect crosslinked complex between TrkA, 125I-NGF never described15xHuber, L.J. Chao, Neurosci Res. 40: 557–563Crossref (107)See References15, unlike 125I-GDNF both Ret Rα.New cell death provided M. Chao (Ithaca, NY, USA), who showed mature oligodendrocytes overexpressing addition induces death, well production c-jun N-terminal kinase (JNK); however, many lines no JNK death. caveat do not normally express countered observation expression might induced inflammation. Moreover, Freda Miller (Montreal, Canada) culture displayed enhanced when cultured presence 2.5 ng ml–1 (low) 100–200 (high) concentrations brain-derived neurotrophic (BDNF); BDNF presumed act through displacement from because kills are sustained 12.5 mM KCl TrkAindependent mechanism. Furthermore, intracellular domain under Tα1 α-tubulin promoter transgenic mice (a collaboration with Phil Barker, Montreal, resulted reduced numbers [and nociceptorspecific dorsal-root ganglion (DRG)] neurones. thus suggested occupancy switches off proapoptotic would concomitantly induced. Occupancy turn, suppress pro-survival effects KCl. Clinching pro-apoptotic it activated now demonstration early developing chick retina prevented antibodies 16xFrade, J.M., Rodriguez-Tebar, A., Barde, Y.A. Nature. 383: 166–168Crossref (593)See 16). However, becauseno increase other p75-expressing injected into eye, appears if events occurring will determine whether its ligation initiate ‘killer’ response.Although activate response similar data neurotrophin-3 (NT-3) have yet described. Intriguing vivo work anti-NT-3 (Xin-Fu Zhou, Adelaide, Australia) NT-3, documented support survival neuroblasts time they withdrawing cycle, requisite co-survival together adult life. It unlikely endogenous co-factor NT-3 mediated 200-fold lower compared 17xDavies, Minichiello, L., Klein, EMBO J. 14: 4482–4489PubMedSee 17). may TrkC, levels TrkC mRNA very low. Perhaps protects against due being weak agonist abundance displace ligands more strongly.The enigmatic question how mediate sympathetic fuelled new data. Recent p21Ras mediates signals example, DRGs rat neurones) others neurones), despite ability Ras Trkexpressing neurones18xBorasio, G.D. Cell Biol. 1993; 121: 665–672Crossref References18,19xNobes, C.D. Tolkovsky, A.M. Eur Neurosci. 7: 344–350Crossref (65)See References19. Further crucial NGF-dependent finding neurofibromin-1 null (neurofibromin inactivates GTPase activity) lose their requirement 20xVogel, K.S. Cell. 82: 733–742Abstract Full Text PDF (119)See 20). even where mediating clear unconventional pathways activated, mitogenactivated protein (MAP) kinases ERK1 ERK2 Ras-dependent effects21xVirdee, K. 2159–2169Crossref (63)See References21,22xVirdee, Neurochem. 67: 1801–1805Crossref References22. So what Ras, replaces fails fulfil survival?David Kaplan utilized tyrosine-site reconstruction defective ‘tyrosine knockout’ Trk show unique receptors, least PC12 cells: same tyrosine residue couples responsible coupling phosphatidylinositol (3′-OH) (PI-3K) (work done Julian Downward, London, UK). Both couplings appear occur two common components, SHC Grb-2, Grb-2 linking further SOS (the GDP–GTP exchange protein) case activation, docking novel (‘protein X’ Fig. 1Fig. 1, identity disclosed) PI-3K activation.Fig. 1An interpretation Kaplan's model cells.View Large Image Download PowerPoint SlideIf true SHC-binding sites could premium limited relative depend on state activities ‘protein downstream collaborators. directly Ras. A cerebellar granule Michael Greenberg (Boston, MA, pharmacological agents activity block insulin sustain survival. labs mediator function Akt (alias PKB)10xGreene, References10, since constitutively active partially reduce after insulin-deprivation, dominant negative increases insulin. test restore blocked. applying inhibitors used neurones, we find arrest neurite outgrowth CPT-cAMP. targets cascades? Is Bcl-2–Bax buffering system [which Alun Davies (St Andrews, UK) essential survival]? signals? And transcriptional post-translational mechanism? At present, there answer suppressed factors any system. unequivocal message emerge meeting must study wish unravel mechanisms survival.What I summarized only small part meeting, viewed prism student given quality presented, probably long wait before results published leading journals.