For example, sciatic nerve injury induces DLK-dependent pro-regenerative responses in dorsal root ganglia (DRG) sensory neurons ( Shin et al., 2012 Shin et al., 2019). However, mice with adult deletion of DLK survive and show no detectable abnormalities ( Pozniak et al., 2013 Le Pichon et al., 2017).В Under traumatic insults, DLK activity is reported to increase and trigger a variety of cellular responses. Constitutive DLK knockout mice die perinatally, and different regions of developing brain display varying degrees of altered axon fibers, abnormal synapses and increased neuronal survival ( Hirai et al., 2006 Hirai et al., 2011 Itoh et al., 2011 Sengupta Ghosh et al., 2011). Several studies have investigated roles of DLK in the development of the nervous system. An emerging theme is that while activation of these kinases triggers seemingly common pathways, the outcome is highly context-specific both in terms of cell types and forms of insults.Д«oth DLK and LZK show broad expression in the nervous system. These MAP3Ks act as upstream kinases for JNK and p38 MAP kinase, and are now known as key players in neuronal stress response network both under acute injury and in chronic neurodegenerative diseases ( Tedeschi and Bradke, 2013 Jin and Zheng, 2019 Asghari Adib et al., 2018 Farley and Watkins, 2018). elegans DLK-1 and Drosophila DLK/Wallenda ( Jin and Zheng, 2019). The mammalian MAP3K DLK (Dual leucine zipper kinase, or MAP3K12) and LZK (Leucine zipper kinase, or MAP3K13) are orthologs of C. The MAPK cascade involves MAP3Ks (MAP kinase kinase kinases), MAP2Ks and MAPKs that together form a phosphorylation relay and activate downstream signaling events in response to external or internal stimuli. Mitogen-activated protein kinase (MAPK) signaling pathways play important roles in neuronal development and function, and aberrant regulation of MAP kinases is associated with many neurological diseases, such as ParkinsonвЂ™s disease (PD), amyotrophic lateral sclerosis (ALS) and AlzheimerвЂ™s disease (AD) ( Thomas and Huganir, 2004 Schellino et al., 2019 Hotamisligil and Davis, 2016 Hollville et al., 2019 Asghari Adib et al., 2018). Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. These two MAP3Ks share similar biochemical activities and undergo auto-activation upon increased expression. The conserved MAP3K Dual-Leucine-Zipper Kinase (DLK) and Leucine-Zipper-bearing Kinase (LZK) can activate JNK via MKK4 or MKK7.

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