Coordinated Regulation of Cholinergic Motor Neuron Traits Through a Conserved Terminal Selector Gene

Nat Neurosci. 2011 Nov 27;15(2):205-14. doi: 10.1038/nn.2989.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Acetylcholinesterase / metabolism
  • Animals
  • Animals, Genetically Modified
  • Caenorhabditis elegans
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / physiology
  • Choline / metabolism
  • Choline O-Acetyltransferase / metabolism
  • Cholinergic Neurons / physiology*
  • Computational Biology
  • Consensus Sequence / genetics
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental / genetics*
  • Gene Expression Regulation, Developmental / physiology
  • Luminescent Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Models, Neurological
  • Molecular Sequence Data
  • Motor Neurons / physiology*
  • Nuclear Proteins / genetics
  • Receptors, Cholinergic / metabolism
  • Trans-Activators / genetics
  • Transcription Factors / genetics*
  • Transcription Factors / physiology

Substances

  • Caenorhabditis elegans Proteins
  • Luminescent Proteins
  • Membrane Transport Proteins
  • Nuclear Proteins
  • Receptors, Cholinergic
  • Trans-Activators
  • Transcription Factors
  • choline transporter
  • unc-3 protein, C elegans
  • Choline O-Acetyltransferase
  • Acetylcholinesterase
  • Choline
  • Acetylcholine