TY - JOUR
T1 - Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene
AU - Kratsios, Paschalis
AU - Stolfi, Alberto
AU - Levine, Michael
AU - Hobert, Oliver
N1 - Funding Information:
We thank Q. Chen for expert assistance in generating transgenic strains; P. Sengupta (Brandeis University) for providing plasmids; many colleagues in the C. elegans community, particularly D. Miller (Vanderbilt University), for providing reporter strains; D. Wu and G. Minevich for bioinformatic analysis; and J. Rand and members of the Hobert laboratory for comments on the manuscript. We are grateful to Caenorhabditis Genetics Center (University of Minnesota) for providing strains. This work was funded by the Muscle Dystrophy Association and the US National Institutes of Health (R01NS039996; R01NS050266). O.H. is an Investigator of the Howard Hughes Medical Institute.
PY - 2012/2
Y1 - 2012/2
N2 - Cholinergic motor neurons are defined by the coexpression of a battery of genes encoding proteins that act sequentially to synthesize, package and degrade acetylcholine and reuptake its breakdown product, choline. How expression of these critical motor neuron identity determinants is controlled and coordinated is not understood. We show here that, in the nematode Caenorhabditis elegans, all members of the cholinergic gene battery, as well as many other markers of terminal motor neuron fate, are co-regulated by a shared cis-regulatory signature and a common trans-acting factor, the phylogenetically conserved COE (Collier, Olf, EBF)-type transcription factor UNC-3. UNC-3 initiated and maintained expression of cholinergic fate markers and was sufficient to induce cholinergic fate in other neuron types. UNC-3 furthermore operated in negative feedforward loops to induce the expression of transcription factors that repress individual UNC-3-induced terminal fate markers, resulting in diversification of motor neuron differentiation programs in specific motor neuron subtypes. A chordate ortholog of UNC-3, Ciona intestinalis COE, was also both required and sufficient for inducing a cholinergic fate. Thus, UNC-3 is a terminal selector for cholinergic motor neuron differentiation whose function is conserved across phylogeny.
AB - Cholinergic motor neurons are defined by the coexpression of a battery of genes encoding proteins that act sequentially to synthesize, package and degrade acetylcholine and reuptake its breakdown product, choline. How expression of these critical motor neuron identity determinants is controlled and coordinated is not understood. We show here that, in the nematode Caenorhabditis elegans, all members of the cholinergic gene battery, as well as many other markers of terminal motor neuron fate, are co-regulated by a shared cis-regulatory signature and a common trans-acting factor, the phylogenetically conserved COE (Collier, Olf, EBF)-type transcription factor UNC-3. UNC-3 initiated and maintained expression of cholinergic fate markers and was sufficient to induce cholinergic fate in other neuron types. UNC-3 furthermore operated in negative feedforward loops to induce the expression of transcription factors that repress individual UNC-3-induced terminal fate markers, resulting in diversification of motor neuron differentiation programs in specific motor neuron subtypes. A chordate ortholog of UNC-3, Ciona intestinalis COE, was also both required and sufficient for inducing a cholinergic fate. Thus, UNC-3 is a terminal selector for cholinergic motor neuron differentiation whose function is conserved across phylogeny.
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U2 - 10.1038/nn.2989
DO - 10.1038/nn.2989
M3 - Article
C2 - 22119902
AN - SCOPUS:84856254786
SN - 1097-6256
VL - 15
SP - 205
EP - 214
JO - Nature neuroscience
JF - Nature neuroscience
IS - 2
ER -