Our lab uses cutting-edge transgenic mouse approaches to investigate basic questions regarding the peripheral and central nervous system development. In particular, we focus on the specific questions below:
Mechanisms Underlying Dopamine Neuron Fate Specification and Neurogenesis
The floor plate, the ventral organizing center in the embryonic neural tube, patterns the neural tube by secreting the potent morphogen Shh. Using genetic fate mapping, our lab has shown that the midbrain floor plate, unlike the hindbrain and spinal cord floor plate, is highly neurogenic and is the source of midbrain dopamine neurons (Joksimovic, et al., 2009, Nature Neuroscience, PNAS). We are interested in understanding morphogen and transcriptional pathways that are involved in DA neuron fate specification and neurogenesis (Nouri and Awatramani, 2017, Development). Further, we are interested in understanding the developmental basis of dopaminergic neuron diversity.
Uncovering DA Neuron Diversity
How midbrain dopamine (DA) neurons underpin a spectrum of apparently unrelated behaviors such as reward and movement, and diseases including Parkinnson’s, addiction, and chronic pain is enigmatic. We hypothesized that the midbrain DAergic system is composed of functionally distinct neuron subtypes, each specialized for a unique subset of functions. For decades, DAergic neurons were classified into three anatomically defined midbrain clusters located in the ventral tegmental area (VTA; A10), the substantia nigra pars compacta (SNc; A9), and retrorubral area (RR; A8). Recently, my lab has defined several putative subtypes of midbrain DA neurons based on their distinct combinatorial gene expression profiles, rather than anatomical location (Poulin et al., 2014, Cell Reports). These initial single-cell profiling based studies provide a first-generation framework for disentangling the DAergic system into its constituent parts. Key unresolved questions are whether these molecularly defined DA neuron subtypes have unique axonal projections, synaptic inputs, and physiological or functional properties. We are developing genetic approaches to access unique DA subtypes towards uncovering their properties in normal and diseased states (Poulin et al., 2018, Nature Neuroscience).
Mechanisms of Schwann Cell Differentiation
MicroRNAs, by modulating gene expression, have been implicated as regulators of various cellular and physiological processes including differentiation, proliferation, and cancer. We have studied the role of microRNAs in Schwann cell (SC) differentiation by conditional removal of the microRNA processing enzymes, Dicer1 and Dgcr8 (Yun et al, 2010, J Neurosci; Lin et al., 2015, JBC) . We reveal that mice lacking Dicer1 or Dgcr8 in SC display a severe neurological phenotype resembling congenital hypomyelination. SC lacking Dicer1 or Dgcr8 are stalled in differentiation at the promyelinating state and fail to myelinate axons. Additionally, mutant SC display aberrant expression of genes such as Shh, normally only expressed in denervated SC. We are beginning to determine the molecular basis of this phenotype. Understanding this will be important not only for myelin-related diseases, but also for peripheral nerve regeneration and SC cancers.