title: Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene.
abstract: 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.
authors: Department of Biochemistry and Molecular Biophysics, Howard Hughes Medical Institute, Columbia University Medical Center, New York, New York, USA. pk2357@columbia.edu
authors: Paschalis
authors: P
authors: Kratsios
authors: Alberto
authors: A
authors: Stolfi
authors: Michael
authors: M
authors: Levine
authors: Oliver
authors: O
authors: Hobert
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000502:physiology; D002794:Choline / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000502:physiology*; D019295:Computational Biology; D016384:Consensus Sequence / Q000235:genetics; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics* / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009046:Motor Neurons / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics; D011950:Receptors, Cholinergic / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology
chemical_list: D029742:Caenorhabditis elegans Proteins; D008164:Luminescent Proteins; D026901:Membrane Transport Proteins; D009687:Nuclear Proteins; D011950:Receptors, Cholinergic; D015534:Trans-Activators; D014157:Transcription Factors; C065637:choline transporter; C112508:unc-3 protein, C elegans; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; D002794:Choline; D000109:Acetylcholine