The cerebral cortex is composed of billions of neurons connected through trillions of synapses. The proper function of the cortex requires appropriate generation of these two classes of neurons, their proper migration into specific layers and the establishment of a balanced number of excitatory and inhibitory synapses between these subpopulations of neurons.
Over the past three decades, the field has made important progress in the identification of the molecular mechanisms regulating neurogenesis and neuronal migration of these various classes of cortical neurons. However, our understanding of the cellular and molecular mechanisms patterning the connectivity of these classes of neurons is still limited. In particular, what are the molecular mechanisms underlying the ability of long-range projecting pyramidal neurons and locally-projecting interneurons to form an axon, for these axons to grow and branch and finally find their appropriate synaptic targets?
One major effort in our lab is focusing on the identification of the molecular mechanisms underlying axon development and patterning of cortical connectivity. We have identified the kinase LKB1 as a ‘master’ regulator of axogenesis (Barnes et al. Cell 2007), axon growth and branching (Courchet, Lewis et al. Cell 2013) in pyramidal long-range projecting neurons.
We are currently focusing on understanding how this LKB1-dependent kinase pathway and some of its 14 potential downstream effector kinases control axon specification, axon growth, branching and presynaptic function. Our current results point to the critical role play by this LKB1-dependent pathway in regulating mitochondria localization and function during axon branching (through presynaptic mitochondria anchoring) and and presynaptic function (through regulation of presynaptic Ca2+ homeostasis- See Kwon et al. PLoS Biology (2016)). We are also exploring the potential cellular and molecular mechanisms anchoring mitochondria at presynaptic boutons.