Definition of the non-canonical MAP-kinase signal pathway mediated by DLK, MKK7, and ERK1/2 connects ApoE-dependent signaling to DLK, which performs important additional functions in synapse formation and neuronal regeneration (Yan et al., 2009; Hammarlund et al., 2009; Shin et al., 2012). However, different from other DLK activities that appear to involve MKK4 and JNKs (Tedeschi and Bradke, 2013), we observed that ApoE-induced stimulation of DLK activates MKK7 and ERK1/2, which then regulates gene transcription via activation of cFos, suggesting that DLK may be a key signaling platform whose precise functional readout depends on the location of that signal and the state of the neurons. Our in vivo experiments in mice show that the downstream signaling mechanisms that we defined normally regulate APP expression, documenting the physiological significance of this pathway. Although the upstream ApoE signal is redundant with other glial signals, redundancy of a function doesn’t mean it is unimportant. Moreover, chronic small changes in the efficacy of a function – such as ApoE2 vs. ApoE3 vs. ApoE4 signaling – could cumulatively cause major effects over the decades of the life of a person.
