Ras/p38 and PI3K/Akt but not Mek/Erk signaling mediate BDNF-induced neurite formation on neonatal cochlear spiral ganglion explants.
Summary of "Ras/p38 and PI3K/Akt but not Mek/Erk signaling mediate BDNF-induced neurite formation on neonatal cochlear spiral ganglion explants."
Neurotrophins participate in regulating the survival, differentiation, and target innervation of many neurons, mediated by high-affinity Trk and low-affinity p75 receptors. In the cochlea, spiral ganglion (SG) neuron survival is strongly dependent upon neurotrophic input, including brain-derived neurotrophic factor (BDNF), which increases the number of neurite outgrowth in neonatal rat SG in vitro. Less is known about signal transduction pathways linking the activation of neurotrophin receptors to SG neuron nuclei. In particular, the p38 and cJUN Kinase (JNK), mitogen-activated protein kinase (MAPK) pathways, which participate in JNK signaling in other neurons, have not been studied. We found that inhibition of Ras, p38, phosphatidyl inositol 3 kinase (PI3K) or Akt signaling reduced or eliminated BDNF mediated increase in number of neurite outgrowth, while inhibition of Mek/Erk had no influence. Inhibition of Rac/cdc42, which lies upstream of JNK, modestly enhanced BDNF induced formation of neurites. Western blotting implicated p38 and Akt signaling, but not Mek/Erk. The results suggest that the Ras/p38 and PI3K/Akt are the primary pathways by which BDNF promotes its effects. Activation of Rac/cdc42/JNK signaling by BDNF may reduce the formation of neurites. This is in contrast to our previous results on NT-3, in which Mek/Erk signaling was the primary mediator of SG neurite outgrowth in vitro. Our data on BDNF agree with prior results from others that have implicated PI3K/Akt involvement in mediating the effects of BDNF on SG neurons in vitro, including neuronal survival and neurite extension. However, the identification of p38 and JNK involvement is entirely novel. The results suggest that neurotrophins can exert opposing effects on SG neurons, the balance of competing signals influencing the generation of neurites. This competition could provide a potential mechanism for the control of neurite number during development.
Affiliation
Surgery/Otolaryngology, UCSD School of Medicine, 9500 Gilman Drive MC0666, La Jolla, CA 92093, USA.
Journal Details
This article was published in the following journal.
Name: Brain research
ISSN: 1872-6240
Pages: 25-34
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22119396
- DOI: http://dx.doi.org/10.1016/j.brainres.2011.10.054
Medical and Biotech [MESH] Definitions
Smad Proteins, Inhibitory
A sub-family of smad proteins that inhibit cell signaling by RECEPTOR-REGULATED SMAD PROTEINS. They form autoinhibitory feedback loops in the TGF-BETA signaling pathway and mediate signaling cross-talk with other signaling pathways
Rho-associated Kinases
A group of intracellular-signaling serine threonine kinases that bind to RHO GTP-BINDING PROTEINS. They were originally found to mediate the effects of rhoA GTP-BINDING PROTEIN on the formation of STRESS FIBERS and FOCAL ADHESIONS. Rho-associated kinases have specificity for a variety of substrates including MYOSIN-LIGHT-CHAIN PHOSPHATASE and LIM KINASES.
Cell Adhesion Molecules, Neuron-glia
Cell adhesion molecules that mediate neuron-neuron adhesion and neuron-astrocyte adhesion. They are expressed on neurons and Schwann cells, but not astrocytes and are involved in neuronal migration, neurite fasciculation, and outgrowth. Ng-CAM is immunologically and structurally distinct from NCAM.
Jaundice, Neonatal
Yellow discoloration of the SKIN; MUCOUS MEMBRANE; and SCLERA in the NEWBORN. It is a sign of NEONATAL HYPERBILIRUBINEMIA. Most cases are transient self-limiting (PHYSIOLOGICAL NEONATAL JAUNDICE) occurring in the first week of life, but some can be a sign of pathological disorders, particularly LIVER DISEASES.
Hyperbilirubinemia, Neonatal
Accumulation of BILIRUBIN, a breakdown product of HEME PROTEINS, in the BLOOD during the first weeks of life. This may lead to NEONATAL JAUNDICE. The excess bilirubin may exist in the unconjugated (indirect) or the conjugated (direct) form. The condition may be self-limiting (PHYSIOLOGICAL NEONATAL JAUNDICE) or pathological with toxic levels of bilirubin.
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