Abstract
Neuronal cell fate determinants establish the identities of neurons by controlling gene expression to regulate neuronal morphology and synaptic connectivity. However, it is not understood if neuronal cell fate determinants have postmitotic functions in synapse pattern formation. Here we identify a novel role for UNC-4 homeobox protein and its corepressor UNC-37/Groucho, in tiled synaptic patterning of the cholinergic motor neurons in Caenorhabditis elegans. We show that unc-4 is not required during neurogenesis but is required in the postmitotic neurons for proper synapse patterning. In contrast, unc-37 is required in both developing and postmitotic neurons. The synaptic tiling defects of unc-4 mutants are suppressed by bar-1/β-catenin mutation, which positively regulates the expression of ceh-12/HB9. Ectopic ceh-12 expression partly underlies the synaptic tiling defects of unc-4 and unc-37 mutants. Our results reveal a novel postmitotic role of neuronal cell fate determinants in synapse pattern formation through inhibiting the canonical Wnt signaling pathway.
Highlights
Formation of a functional neuronal circuit starts from the establishment of individual neuronal identities
We showed that the cell fate determinants of A-type cholinergic motor neurons, UNC-4/Hox and its corepressor UNC-37/Groucho, have novel roles in the postmitotic neurons to control the tiled presynaptic innervation pattern
Previous studies in both vertebrate and invertebrate systems have demonstrated that sustained expression of neuronal cell fate determinants in the differentiated neurons is required to maintain effector gene expression for the functionality of neurons (Altun-Gultekin et al, 2001; Carney et al, 2013; Cheng et al, 2004)
Summary
Formation of a functional neuronal circuit starts from the establishment of individual neuronal identities. The postembryonic unc-4 knockdown by up-shifting the growth temperature from 16°C to 25°C at the L1 stage resulted in severe synaptic tiling defects (Figures 2E and 2F) Together, this suggests that unc-4 is required in the postmitotic DA8 and DA9 neurons in which the cell fates are already set. Similar to UNC-4::AID::BFP, we observed DA neuron-specific loss of BFP signal (Figure 3 – Supplemental 2D) and severe synaptic tiling defects in unc-37(miz36); mizSi3 animals grown continuously on the K-NAA-containing plates (Figures 3H and 3K), suggesting that unc-37 functions cell autonomously in DA neurons for synaptic tiling. Consistent with our idea, bar-1(ga80) partially suppressed the synaptic tiling defect of unc-4 mutants (Figures 4F and 4G) This result suggests that UNC-4 inhibits the canonical Wnt signaling for the expression of multiple genes including ceh-12 to control synaptic tiling. We were unable to examine unc-37(e262); bar-1(ga80) double mutants due to the synthetic lethal phenotype (data not shown). 356
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