[BIO Colloquium] Motor Neuron Gene Regulatory Network and Cholinergic Neurotransmitter Programming
  • Seunghee Lee, Ph.D. (Seoul National University)
  • SLS Colloquia / Sep 30th 04:00 pm / AMRB 113

The establishment of correct neurotransmitter characteristics is an essential step of neuronal fate specification in CNS development. However, very little is known about how a battery of genes involved in the determination of a specific type of chemical-driven neurotransmission is coordinately regulated during vertebrate development. We investigated the gene regulatory networks that specify the cholinergic neuronal fates in the spinal cord and forebrain, specifically, spinal motor neurons (MNs) and forebrain cholinergic neurons (FCNs). We found that Isl1 forms two related, but distinct types of complexes, the Isl1-Lhx3-hexamer in MNs and the Isl1-Lhx8-hexamer in FCNs. Interestingly, our genome-wide ChIP-seq analysis revealed that the Isl1-Lhx3-hexamer binds to a suite of cholinergic pathway genes encoding the core constituents of the cholinergic neurotransmission system, such as acetylcholine synthesizing enzymes and transporters. Interestingly, STAT3-binding motif is highly enriched in the Isl1-Lhx3?hexamer?bound peaks. We also found that a transcriptionally active form of STAT3 is expressed in embryonic motor neurons and that STAT3 associates with the MN?hexamer, enhancing the transcriptional activity of the MN?hexamer in an upstream signal-dependent manner. Correspondingly, STAT3 was needed for motor neuron differentiation in the developing spinal cord. Together, our studies show a shared molecular mechanism that determines the cholinergic neuronal fate in the spinal cord and forebrain, and uncover crucial gene regulatory mechanisms that couple MN?hexamer and STAT-activating extracellular signals to promote motor neuron differentiation in vertebrate spinal cord.