New directions in subtype-specific growth cone molecular machinery for circuit wiring, maintenance, and potentially disease


novel GC biology

A central question in neuroscience is how function-specific circuitry is established, maintained, and modified for remarkably diverse neuronal connections — a question that has remained inaccessible in multiple core aspects, including the in vivomolecular composition of growth cones (GCs) of specific neuronal subtypes at specific developmental stages. Because GCs often navigate 103 or 104 cell body diameters from their parent somata (105 in humans), capacity for autonomous behavior without feedback from the nucleus would enable more rapid and spatially precise responses to extracellular cues. Such autonomous function has been documented for decades, with experiments that showed accurate growth of axons after severing connections with the cell body. GC pathfinding functions have since been shown to depend on tightly regulated local protein synthesis — GCs have a localized transcriptome and translation of specific mRNA species is regulated by exposure to extracellular cues. However, most current knowledge of GC biology has been identified in vitro, often with heterogeneous populations of neurons. Our laboratory has developed an innovative new approach to isolate GCs from the developing brain in a stage- and subtype-specific fashion, as access to specific populations of GCs during normal or perturbed development will substantially elucidate molecular bases of cortical circuit formation. This approach, combined with state-of-the art RNA-sequencing and mass spectrometry, enables unbiased, high-throughput identification of molecular networks that directly implement neuronal circuit formation in the CNS. Elucidating these local molecular controls over GC biology is therefore of substantial importance toward understanding development, organization, maintenance, and disease of subtype-specific circuitry.

Selected publications

  • Poulopoulos , A., Murphy, A.J., Ozkan, A., Davis, P., Hatch, J., Kirchner, R., Macklis, J.D. Subcellular transcriptomes and proteomes of developing axon projections in the cerebral cortex. Nature (2019) Jan;565(7739):356-360. Pubmed