Sensory Neuron Fates Are Distinguished by a Transcriptional Switch that Regulates Dendrite Branch Stabilization

Abstract

SUMMARY Sensory neurons adopt distinct morphologies and functional modalities to mediate responses to specific stimuli. Transcription factors and their downstream effectors orchestrate this outcome but are incompletely defined. Here, we show that different classes of mechanosensory neurons in C. elegans are distinguished by the combined action of the transcription factors MEC-3, AHR-1, and ZAG-1. Low levels of MEC-3 specify the elaborate branching pattern of PVD nociceptors, whereas high MEC-3 is correlated with the simple morphology of AVM and PVM touch neurons. AHR-1 specifies AVM touch neuron fate by elevating MEC-3 while simultaneously blocking expression of nociceptive genes such as the MEC-3 target, the claudin-like membrane protein HPO-30, that promotes the complex dendritic branching pattern of PVD. ZAG-1 exercises a parallel role to prevent PVM from adopting the PVD fate. The conserved dendritic branching function of the Drosophila AHR-1 homolog, Spineless, argues for similar pathways in mammals.

Centrosomin represses dendrite branching by orienting microtubule nucleation

“…Class--specific dendrite targeting is regulated via the activity of transmembrane adhesion proteins. For example, in C. elegans, class--specific expression patterns of the transcription factors MEC--3, AHR--1, and ZAG--1 regulate the morphology of mechanosensory neurons, and MEC--3 promotes differential expression of the Claudin--like membrane protein HPO--30 to enable lateral branch stabilization 10 .…”

Dendritic diversification through transcription factor-mediated suppression of alternative morphologies

“…Transcription factors may suppress alternative programs of differentiation and promote neuronal diversity by direct repression of other transcription factors, repression of their downstream target genes, or by competitive binding of common cofactors to block transcription factor function Borromeo et al, 2014;Gordon and Hobert, 2015). Differential expression levels of the same transcription factor can also drive distinct morphology, identity and connectivity to further increase diversity in the nervous system (Grueber et al, 2003;Chen et al, 2006;Dasen et al, 2008;Smith et al, 2013). It has been proposed that such transformations from one cell type, or cell characteristic, to another by mutations in terminal selector genes might provide a basis for the evolutionary diversification of cell types in the nervous system (Arlotta and Hobert, 2015).…”

Transcription factors and effectors that regulate neuronal morphology

“…In mec-3 mutants, the PVD cell body position and axon are normal, but PVD dendrites display dramatic growth defects and fail to initiate secondary branches (Smith et al, 2010;Tsalik et al, 2003). These defects are rescued by PVD-specific expression of MEC-3 (Smith et al, 2013).…”

“…A recent study identified hpo-3/claudin as a downstream effector of MEC-3 in regulating PVD morphology (Smith et al, 2013). Miller and colleagues compared the mRNA profiles of PVD neurons from wild-type animals with those from mec-3 mutants and identified many putative MEC-3 targets, including hpo-30/ claudin.…”

“…How does MEC-3 regulate dendritic morphology in a cell-type specific manner? Smith et al demonstrate that in the AVM light touch neuron, the bHLH transcription factor AHR-1 downregulates MEC-3 targets that promote a PVD morphology, while simultaneously promoting expression of mec-3 itself (Smith et al, 2013). In ahr-1 mutants, the AVM neuron is transformed into a PVD-like neuron both morphologically and functionally; the morphological change is mec-3 dependent.…”