Abstract:
The long-term goals of the work I will discuss are to three-fold– in development, disease, and regeneration: 1) to elucidate central molecular mechanisms controlling development and diversity of cerebral cortex function-specific circuitry, thus organization and evolution (to some extent) of the cerebral cortex; 2) to identify causes/mechanisms of developmental and selective neuron subtype vulnerability in many neurodegenerative disorders; and 3) to elucidate and potentially overcome blocks to CNS regeneration. The specificity, modification, and function of such circuitry underlies how the brain-nervous system senses, integrates, moves the body, thinks, functions with precision, malfunctions with specificity in disease, degenerates with circuit specificity, might be regenerated, and/or might be modeled in culture, but has been previously inaccessible in multiple core aspects. What actually implements and maintains circuit specificity is a key, core issue from developmental specificity of circuits, to developmental abnormalities and disease, proper function (or dysfunction) and circuit type-specific molecular regulators and drugs, selective neuron type vulnerability of degeneration (e.g. in MND/ALS, Huntington’s, Parkinson’s diseases), regeneration (or typical lack thereof) in the CNS for spinal cord injury, and mechanistic and therapeutic modeling of disease using human induced pluripotent stem cell (hiPS)-derived neurons. Growth cones (GCs) are the subcellular structures that “build” circuits with specificity and mature into synapses, where human genomic risk associations are showing up in neuropsychiatric diseases such as schizophrenia, autism, bipolar disorder, developmental intellectual disabilities, but we know little about the diversity and specialization of circuit-specific GCs or synapses. I will present a brief integration of recent work investigating subtype-, stage-, and target-specific GCs and synapses in development, neuronal and circuit diversity, disease, regeneration, and newly enabled hiPS-based fused organoid “assembloids” to address these critical gaps in knowledge. I will dabble a bit in discussing evolution here and there. We have developed and integrate several new approaches (e.g. subtype- and stage-specific subcellular RNA, protein, translational regulation, “specialized” ribosome analysis of GCs / synapses directly from brains; mosaic genetic circuit analysis; hiPS “assembloids” with somewhat selective connectivity) to investigate basic “framing rules” of diverse function-enabling CNS circuitry, potentially explain selective vulnerability in developmental and degenerative nervous system diseases, and potentially enable CNS regeneration.