ERK activation and expression of neuronal cell cycle markers in the hippocampus after entorhinal cortex lesion.
Current findings suggest that neuronal cell death is frequently associated with the aberrant expression of cell cycle-regulatory proteins in postmitotic neurons. Aberrant cell cycle reentry has been implicated in diverse neurodegenerative conditions, including Alzheimer's disease (AD). Previously we reported that the appearance of cell cycle markers in postmitotic neurons of the entorhinal cortex (EC) after excitotoxic hippocampal damage is associated with the expression of phospho-tau and amyloid precursor protein (APP). However, the question of the signaling pathway involved in this cell cycle reentry remains unresolved. Differentiated neurons use the molecular mechanisms initially acquired to direct cell proliferation, such as the Ras-extracellular signal-regulated kinase (ERK1/2) pathway, to regulate synaptic plasticity. In this work we explored whether ERK1/2-related signaling might contribute to the cell cycle reentry in hippocampal neurons after a unilateral EC lesion. We showed that, within the first 24 hr after hippocampal deafferentation, numerous neurons expressed phospho-ERK1/2, concomitantly with the gradual increases in cyclin D1 and cyclin B immunoreactivity in the dentate gyrus and hilus. Several of these immunopositive cells to phospho-ERK1/2 and cyclin B in hippocampus are postmitotic neurons, insofar as they are positive to NeuN. The intracisternal administration of U0126 (an MEK inhibitor), previous to the excitotoxic lesion, decreased the activation of ERK1/2 and the expression of cyclin D1 and cyclin B in the hippocampus. The present findings support the notion that ERK1/2 plays a role in cell cycle reactivation in mature neurons efferently connected to the lesion site.
Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México D.F., México.
Karina
K
Hernández-Ortega
Clorinda
C
Arias
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle / Q000502:physiology*; D018728:Entorhinal Cortex / Q000293:injuries; D004789:Enzyme Activation; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3