Coordinated regulation of cholinergic motor neuron traits through a conserved terminal selector gene

Abstract

Cholinergic motor neurons are defined by the co-expression of a battery of genes which encode 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 initiates and maintains expression of cholinergic fate markers and is sufficient to induce cholinergic fate in other neuron types. UNC-3 furthermore operates 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, is 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.

Patterning of sexually dimorphic neurogenesis in the Caenorhabditis elegans ventral cord by Hox and TALE homeodomain transcription factors

“…Consistent with this, an unc-3::mCherry reporter is not expressed in hermaphrodite VC neurons or in male CAs or CPs (Kratsios et al, 2012, and our unpublished observations). We wondered if lin-39 is required for serotonergic marker expression outside of Pn.aap, and find that to be the case: lin-39(n1760) fully suppresses the ectopic tph-1::gfp expression in the ventral cord in unc-3(e151) mutants of both sexes (hermaphrodites, n ¼ 102, males n ¼ 127).…”

“…1), from assuming Pn.aap fates (Prasad et al, 2008;Kratsios et al, 2012). We find that lin-39 is required for serotonergic fate even outside Pn.aap descendants, suggesting that lin-39 may confer serotonergic competence on all Pn.aaderived cells, with this competence limited by other regulators of cell fate such as unc-3.…”

Genome-wide analysis of the bHLH gene family in planarians identifies factors required for adult neurogenesis and neuronal regeneration

“…coe genes are conserved in metazoans and are known to play roles in neuronal specification, migration, axon guidance, dendritogenesis, neuronal subtype specification (Wightman et al, 1997;Dubois et al, 1998;Prasad et al, 1998;Garel et al, 2000;Pozzoli et al, 2001;GarciaDominguez et al, 2003;Hattori et al, 2007;Jinushi-Nakao et al, 2007;Crozatier and Vincent, 2008;Demilly et al, 2011;Kratsios et al, 2012), and cellular reprogramming (Richard et al, 2011). In planarians, coe knockdown led to a failure of animals to connect the cephalic ganglia.…”

TMC-1 attenuates C. elegans development and sexual behaviour in a chemically defined food environment

“…tmc-1 was reported to be expressed in sensory neurons, cholinergic ventral cord neurons and additional unidentified head, motor and interneurons 15,22 . However, which of these TMC-1-expressing tissues regulate development was not obvious.…”