Specificity and defects of neuronal circuitry in health and disease: Growth cone proteomes and RNA
Many devastating developmental, neurodegenerative, and acquired central nervous system diseases and injuries primarily affect long-distance connection nerve cells of the cerebral cortex, whose “wiring” of their circuits is performed by extending tiny structures called “growth cones” (GCs). Almost nothing is known about the actual molecules (in particular, proteins and RNAs) that control each different kind of GC to build specific circuitry that makes us think, move, sense, and behave, and nothing is known about what might almost certainly go wrong with GCs in disease. We successfully developed an entirely new approach to discover this entire GC biology for the first time in the world. We propose its first application to two human disease mouse models (for the childhood developmental disorder “agenesis of the corpus callosum”, AgCC; and for Huntington’s disease, HD– mis-wiring is known or suspected to be critically involved in pathology in both disorders). Using specific circuit GCs of normal and of already available genetically engineered mice with correct human disease gene variants and known disease abnormalities, we propose experiments to discover specific molecular systems in GCs that build normal brains, and that cause mis-wiring in disease. We propose to investigate effects of human mutations that cause AgCC in children, using GCs of specific mouse neurons. We also propose to investigate specific neurons’ GCs with a human Huntington’s disease gene variant. Success in the proposed experiments will pave the way for broad application of this approach for discovery in disease–toward both understanding and therapy. Brain circuitry and GC biology is central to human neurologic and psychiatric disease, but direct investigation has been impossible before this unique, innovative work.