Roles of a novel MAPKKK in axonal responses to injury in the mammalian CNS

University Of California, San Diego, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): The limited axonal growth after central nervous system (CNS) injury is the principal cause of no or limited functional recovery after spinal cord injury in humans. While earlier studies emphasized the importance of neuron-extrinsic mechanisms, recent development in the field highlighted the central role of neuron-intrinsic control of axon growth and regeneration after CNS injury. Among neuron-intrinsic regulators, there are factors that sense and mediate the injury signals to elicit diverse responses in differen neuronal populations. Recent discoveries in model organisms such as the nematode and the fruit fly indicate a critical role for a MAP kinase kinase kinase (MAPKKK, or MAP3K), DLK, in axon degeneration and regeneration. There are two sequence homologues in mammals: DLK (also known as MAP3K12) and LZK (also known as MAP3K13). Several studies indicate that mammalian DLK/MAP3K12 is important in axonal responses to injury. Little is known about the other homologue LZK/MAP3K13. Our preliminary studies strongly indicate that LZK regulates axon growth. Here we test the hypothesis that LZK is an important regulator of axonal responses to injury in the mammalian nervous system. We will test the effect of loss of function and gain of function genetic manipulations of LZK in different injury models. In this context, we will also examine any functional redundancy or synergy between DLK and LZK by combined genetic manipulations. To this end, we have generated both loss and gain of function alleles for DLK and LZK in mice. We will examine injury-induced axon degeneration, regeneration (axonal growth from injured neurons) and sprouting (axonal growth from uninjured neurons) with a number of injury models in the CNS, supplemented by injury models in the PNS (peripheral nervous system). Finally, we will examine potential interaction between the LZK and DLK signaling pathways with other neuron- intrinsic (e.g. PTEN) regulators of axon growth. Together, these studies will reveal the endogenous role of the LZK and DLK signaling, and assess the therapeutic potential of activating LZK and DLK signaling in promoting axonal repair after CNS injury.