Development and maintenance of Axon/Dendrite identity
Neurons are the basic signaling units of the nervous system. They have two distinct compartments, axons and dendrites, which differ in molecular composition, in morphology, in growth rate, and in synaptic polarity from one another. The establishment and maintenance of neuronal polarity is of fundamental importance to the function of the nerves system and is highly relevant to certain neurological disorders. However, the developmental mechanism underlying the neuronal polarization remains elusive.
Our lab is interested in exploring the potential mechanisms for axon/dendrite formation. We have been using primary hippocampal culture as an in vitro model for studying axon/dendrite polarization. We, together with Dr. Mu-Ming Poo's lab, have demonstrated that BDNF, a secreted neurotrophin essential for the survival and differentiation of many neuronal populations, serves as a self-amplifying autocrine factor in promoting axon formation by triggering two nested positive-feedback mechanisms. First, BDNF elevates cytoplasmic cAMP and protein kinase A (PKA) activity, which triggers further secretion of BDNF and membrane insertion of its receptor TrkB. Second, BDNF/TrkB signaling activates PI3-kinase that promotes anterograde transport of TrkB in the putative axon, further enhancing local BDNF/TrkB signaling. We also discovered a new mechanism for E3 ubiquitin ligase Smurf1 to switch its substrate preference between two proteins of opposing actions on axon development. We found that polarizing factors induce Smurf1 phosphorylation at a PKA site Thr306, leading to reduced degradation of polarity protein Par6 and increased degradation of growth-inhibiting RhoA. Preventing Smurf1 Thr306 phosphorylation reduces axon formation in cultured hippocampal neurons and impairs polarization of cortical neurons in vivo.
In addition to the chemical (trophic) influence, mechanical environments certainly play a role in neuronal differentiation. In the future, we would like to explore and characterize the role of secreted factors on neuronal differentiation during brain development and also aim at unveiling the missing links of physical factors participating in neuronal polarization of neurons and neural stem cells.