An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons

Abstract

A core principle of nervous system organization is the diversification of neuron classes into subclasses that share large sets of features but differ in select traits. We describe here a molecular mechanism necessary for motor neurons to acquire subclass-specific traits in the nematode Caenorhabditis elegans. Cholinergic motor neuron classes of the ventral nerve cord can be subdivided into subclasses along the anterior-posterior (A-P) axis based on synaptic connectivity patterns and molecular features. The conserved COE-type terminal selector UNC-3 not only controls the expression of traits shared by all members of a neuron class, but is also required for subclass-specific traits expressed along the A-P axis. UNC-3, which is not regionally restricted, requires region-specific cofactors in the form of Hox proteins to co-activate subclass-specific effector genes in post-mitotic motor neurons. This intersectional gene regulatory principle for neuronal subclass diversification may be conserved from nematodes to mice.DOI: http://dx.doi.org/10.7554/eLife.25751.001

A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

“…4F). Second, lin-39 expression in these MNs is not affected by unc-3 [22]. Lastly, we found that lin-39 acts cell-autonomously as cholinergic MNspecific RNAi against lin-39 in unc-3 (n3435); flp-11::gfp animals resulted in a significant reduction of ectopic flp-11 expression ( Fig.…”

“…4A) for several reasons. First, lin-39 is co-expressed with unc-3 in wild-type cholinergic MNs at the mid-body region of the VNC [22], but is unable to induce VD or VC terminal identity genes ( Fig. 4F).…”

“…What is the function of LIN-39 in wild-type cholinergic MNs of the VNC? Our previous findings suggested that LIN-39 and UNC-3, together with another mid-body Hox protein, MAB-5 (Antp/Hox6-8) [43], act synergistically to control expression of two terminal identity genes (unc-129, ortholog of human BMP; del-1 / Degenerin-like sodium channel [ortholog of human SCNN1G]) [22]. To test the extent of this synergy, we examined in lin-39 null animals the expression of 4 additional cholinergic MN terminal identity genes known to be controlled by UNC-3 (acr-2 / nicotinic acetylcholine receptor; dbl-1 / DPP/BMP-like; nca-1 / sodium channel [ortholog of human NALCN], slo-2 / potassium sodium-activated channel [ortholog of human KCNT1]) [23].…”

“…UNC-3, the sole C. elegans ortholog of the Collier/Olf/Ebf (COE) family of TFs, is selectively expressed in all sex-shared cholinergic MNs of the nerve cord ( Fig. 1B) [22][23][24][25][26].Animals lacking unc-3 display striking locomotion defects [27]. UNC-3 is known to directly activate a large battery of terminal identity genes expressed either in all sex-shared cholinergic MNs (e.g., the NT identity genes unc-17/ VAChT and cha-1/ ChAT), or in certain subtypes (e.g., ion channels, NT receptors, signaling molecules) [23] ( Fig.…”

“…UNC-3, the sole C. elegans ortholog of the Collier/Olf/Ebf (COE) family of TFs, is selectively expressed in all sex-shared cholinergic MNs of the nerve cord ( Fig. 1B) [22][23][24][25][26].…”