Elucidating the role of MKK4 in neuronal apoptosis

Brain injury and neurological conditions are often associated with the excessive loss of neurones through apoptosis. In the brain, apoptosis is triggered by the activation of the c-Jun N-terminal protein kinase (JNK) signalling pathway by two mitogen-activated protein kinases (MAPKs): MKK4 and MKK7. While both proteins activate JNK in response to various extracellular stimuli, the biological functions of MKK4 and MKK7 in neuronal cell death remain to be identified. To advance our knowledge, I have developed two novel models of neuronal apoptosis using primary cultures of cortical neurones (MECN) and cerebellar granule neurones (CGN) in which MKK4 expression can be deleted. The absence of MKK4 significantly impedes stress-induced caspase-3 activation in both cell types and partially protects neurones against stress-induced death and apoptosis. Furthermore, the loss of MKK4 leads to the inhibition of JNK3 activation following stress, and causes a marked decrease in the expression of c-Jun, a major target of JNK. This study suggests that MKK4 mediates stress-induced apoptosis in neurones through the activation of the JNK3/c-Jun pathway.