[SY1.0]: Regulation of spinal neuron cell identity

During embryonic development specific subclasses of neurons are specified within ventral neural tube that participate in the complex circuitry controlling movement. Many of these separate neuronal classes express unique combinations of transcription factors that assemble into higher order complexes to regulate gene expression. A prototypical example is the LIM-class transcription factor family, which binds to nuclear LIM interactor (NLI, Ldb, clim) in specific ratios to form ternary regulatory complexes. We examined how the dosage of LIM homeodomain proteins Isl1 and Isl2, and LIM-only protein LMO4 influence the function of interrelated NLI-complexes to regulate spinal motor neuron (MN), V2a interneuron (IN), and V2b IN development. Reducing the overall levels of Isl-proteins using a graded series of mutations in Isl1 and Isl2 caused MNs to acquire V2a IN characteristics. LMO4 was found to antagonize Isl-proteins by displacing them from NLI, and cooperate with SCL and Gata2 to generate V2b INs—prompting us to wonder why MNs express LMO4. We found that the negative actions of LMO4 on MN generation were gated by the levels of Isl protein in cells. Our findings indicate that MN, V2a, and V2b IN fates are sensitive to the relative stoichiometries of the constituent components and that LMO4 helps to set the thresholds.