Defining CAMK4 transcript isoforms for axonal plasticity

影响轴突生长作为促进神经恢复和减轻病理的一种手段

Affecting axonal growth as a means to enhance recovery and alleviate pathology in conditions of nervous system injury, insult, or disease is a major goal for the healthcare and biomedical research endeavors. Significant effort is directed at inducing neural plasticity to enhance axonal growth to establish functionally- adaptive connections. However, these efforts must also prevent, and not induce, maladaptive plasticity, a balance which requires a clear understanding of the processes regulating axon growth. We have recently determined that the mechanisms of the two major forms of axon growth in the adult nervous system – growth of injured axons (Regeneration) and that of non-injured axons (Collateral Sprouting - CS) – differ significantly and involve distinct transcriptional profiles. We have identified Camk4 as a gene necessary for Collateral Sprouting but not involved in Regeneration. We have further determined that during CS, Camk4 expression is regulated not at the coding sequence, but at the 3’ UTR. Camk4, and particularly Camk4 with this novel sprouting-related 3’ UTR, is expressed in neurons known to have a high degree of constitutive plasticity capacity such as sensory nociceptors, hippocampus, cerebellum, and cortex. These findings point to additional potential mechanisms by which CamK4 may be acting, and also opens additional potential therapeutic targets. However, tools to examine those mechanisms are lacking. We aim to determine the range and character of transcript isoforms expressed by neurons at basal state and during plasticity (regeneration and sprouting). These data will have significant value on their own, but will be used here to direct the design of a novel mouse with conditional-deletion of the novel long-isoform of the 3’ UTR without disrupting the protein coding sequence. This will allow us to determine the role of this important transcript segment in protein expression and localization, and examine other protein-independent functions which may exist. Although vital for mechanistic studies of axonal plasticity, these data and the new mice will also be useful for any cells which express Camk4 and use the novel long 3’ UTR (e.g., testicular cells, kidney podocytes, adipocytes, T cells, etc.) and we have established collaborative arrangements with a range of labs that would like to use these new mice in their research.