Axon guidance is a critical step in the development of the central nervous system. Mounting evidence suggests that axon guidance is disrupted in many patients suffering from several neurodevelopmental disorders, including schizophrenia and autism. The guidance cue netrin-1 and netrin receptor DCC regulate axon guidance by modulating the growth cone cytoskeleton, but the mechanisms are not fully understood. We recently identified the E3 ubiquitin ligase TRIM9 as a novel binding partner of DCC and a regulator of axon guidance and the cytoskeleton. We also have preliminary data showing that the highly similar protein TRIM67 interacts with DCC and the actin regulatory protein VASP, and is necessary for netrin-dependent axon branching. This proposal will test our hypothesis that TRIM9 and TRIM67 coordinate to regulate the downstream effects of netrin-1 dependent axon guidance.
Our first aim will be to identify and confirm TRIM67 direct interactions with DCC and Ena/VASP actin regulatory proteins and their colocalization at filopodia tips.
Our second aim i s to define the role of TRIM67 in netrin-dependent axon morphogenesis.
Our third aim will focus on identifying axon guidance defects that occur upon deletion of TRIM67 in vitro, using novel microfluidic devices, as well as defects that occur in vivo using histological analysis. These experiments will help to further elucidate mechanisms of neuronal development.
A variety of neurological disorders including schizophrenia and autism can arise from disruptions in neuronal development and connectivity. The experiments in this proposal will illuminate the role of the neuronally- enriched E3 ubiquitin ligase TRIM67 in regulating neuronal integration into brain networks. A greater understanding of cellular and molecular mechanisms of neuronal development is critical for the future development of diagnostics and treatments for diseases of the central nervous system.
| Boyer, Nicholas P; Monkiewicz, Caroline; Menon, Shalini et al. (2018) Mammalian TRIM67 Functions in Brain Development and Behavior. eNeuro 5: |
| Boyer, Nicholas P; Gupton, Stephanie L (2018) Revisiting Netrin-1: One Who Guides (Axons). Front Cell Neurosci 12:221 |
