BDNF activated TrkB/IRR receptor chimera promotes survival of sympathetic neurons through Ras and PI-3 kinase signaling.
Insulin receptor-related receptor (IRR) expression is tightly coupled to the nerve growth factor (NGF) receptor, TrkA, throughout development. Expression of both receptors is primarily localized to neural crest derived sensory and sympathetic neurons. In contrast to TrkA, however, the physiological ligand for IRR is unknown. To analyze the intracellular signaling and potential function of the orphan IRR in neurons, an adenovirus expressing a TrkB/IRR chimeric receptor was used to infect cultured mouse superior cervical ganglion neurons that normally require NGF for survival. Brain derived neurotrophic factor (BDNF)-activated TrkB/IRR induced neuronal survival. We utilized numerous receptor mutants in order to identify the intracellular domains of IRR necessary for signaling and neuron survival. Finally, we employed adenovirus encoding dominant negative forms of the extracellular signal-regulated kinase (ERK) signaling cascade to demonstrate that IRR, like TrkA, requires ras activation to promote neuron survival. Therefore, by use of the chimeric TrkB/IRR receptor, we have demonstrated the ability of IRR to elicit activation of signaling cascades resulting in a biological response in superior cervical ganglion (SCG) neurons.
Kelly-Spratt
Karen S
KS
Center For Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75235-9133, USA.
Klesse
Laura J
LJ
Parada
Luis F
LF
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D018929:Cell Culture Techniques; D002470:Cell Survival; D011905:Genes, ras; D051379:Mice; D008810:Mice, Inbred C57BL; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D015290:Second Messenger Systems; D017783:Superior Cervical Ganglion / Q000201:enzymology / Q000378:metabolism*; D013997:Time Factors
D019208:Brain-Derived Neurotrophic Factor; D011993:Recombinant Fusion Proteins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D020813:Receptor, trkB; C066542:insulin receptor-related receptor