Subject(s)
Interneurons/cytology , Interneurons/drug effects , Leukemia Inhibitory Factor/pharmacology , Synapses/drug effects , Visual Cortex/cytology , Animals , Animals, Newborn , Axons/drug effects , Brain-Derived Neurotrophic Factor/pharmacology , Calcium/metabolism , Dendrites/drug effects , In Vitro Techniques , Interneurons/metabolism , Mitogen-Activated Protein Kinase Kinases/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neuropeptide Y/genetics , Neuropeptide Y/metabolism , Organ Culture Techniques , Rats , Rats, Long-Evans , Shaw Potassium Channels/genetics , Shaw Potassium Channels/metabolism , Synaptotagmin II/genetics , Synaptotagmin II/metabolism , Time FactorsABSTRACT
The 30-amino acid peptide Y-P30, generated from the N-terminus of the human dermcidin precursor protein, has been found to promote neuronal survival, cell migration and neurite outgrowth by enhancing the interaction of pleiotrophin and syndecan-3. We now show that Y-P30 activates Src kinase and extracellular signal-regulated kinase (ERK). Y-P30 promotes axonal growth of mouse embryonic stem cell-derived neurons, embryonic mouse spinal cord motoneurons, perinatal rat retinal neurons, and rat cortical neurons. Y-P30-mediated axon growth was dependent on heparan sulfate chains. Y-P30 decreased the proportion of collapsing/degenerating growth cones of cortical axons in an Src and ERK-dependent manner. Y-P30 increased for 90 min in axonal growth cones the level of Tyr418-phosphorylated Src kinase and the amount of F-actin, and transiently the level of Tyr-phosphorylated ERK. Levels of total Src kinase, actin, GAP-43, cortactin and the glutamate receptor subunit GluN2B were not altered. When exposed to semaphorin-3a, Y-P30 protected a significant fraction of growth cones of cortical neurons from collapse. These results suggest that Y-P30 promotes axonal growth via Src- and ERK-dependent mechanisms which stabilize growth cones and confer resistance to collapsing factors.
Subject(s)
Axons/drug effects , Growth Cones/drug effects , Neural Stem Cells/drug effects , Neurons/cytology , Peptides/pharmacology , Actins/metabolism , Animals , Cell Proliferation/drug effects , Cells, Cultured , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Dose-Response Relationship, Drug , Embryo, Mammalian , GAP-43 Protein/metabolism , Gene Expression Regulation/drug effects , MAP Kinase Signaling System/drug effects , Mice , Molecular Imaging , Neurons/drug effects , Organ Culture Techniques , Rats , Rats, Long-Evans , Retina/cytology , Retina/drug effects , Semaphorin-3A/metabolismABSTRACT
The synRas transgenic mice express constitutively activated Valin12-Harvey Ras in postnatal neocortical pyramidal neurons. This leads to somatodendritic hypertrophy, higher densities of spines and synapses, and an enhancement of synaptic long-term potentiation associated with an increased glutamate receptor-mediated activity. It was less clear how the interneurons respond to these alterations, and this prompted the quantitative assessment of interneuron neurochemistry. Interneurons rarely expressed the transgene, however, several interneuron types displayed a transient somatic hypertrophy. Furthermore, NPY mRNA expression was persistently increased as were the laminar percentages of labeled neurons. The expression of parvalbumin and voltage-gated potassium channels Kv3.1b/3.2 was unchanged. A significant decline of GAD-67, but not GAD-65, mRNA expressing neurons was observed in layer VI in animals older than P60. This suggested that subtle deficits in inhibition and enhanced excitation evoke the interneuronal changes in the synRastransgenic mouse cortex.
