Abstract
Many neuronal identity regulators are expressed in distinct populations of cells in the nervous system, but their function is often analyzed only in specific isolated cellular contexts, thereby potentially leaving overarching themes in gene function undiscovered. We show here that the Caenorhabditis elegans Prop1-like homeobox gene unc-42 is expressed in 15 distinct sensory, inter- and motor neuron classes throughout the entire C. elegans nervous system. Strikingly, all 15 neuron classes expressing unc-42 are synaptically interconnected, prompting us to investigate whether unc-42 controls the functional properties of this circuit and perhaps also the assembly of these neurons into functional circuitry. We found that unc-42 defines the routes of communication between these interconnected neurons by controlling the expression of neurotransmitter pathway genes, neurotransmitter receptors, neuropeptides, and neuropeptide receptors. Anatomical analysis of unc-42 mutant animals reveals defects in axon pathfinding and synaptic connectivity, paralleled by expression defects of molecules involved in axon pathfinding, cell-cell recognition, and synaptic connectivity. We conclude that unc-42 establishes functional circuitry by acting as a terminal selector of functionally connected neuron types. We identify a number of additional transcription factors that are also expressed in synaptically connected neurons and propose that terminal selectors may also function as 'circuit organizer transcription factors' to control the assembly of functional circuitry throughout the nervous system. We hypothesize that such organizational properties of transcription factors may be reflective of not only ontogenetic, but perhaps also phylogenetic trajectories of neuronal circuit establishment.
Highlights
Individual gene regulatory factors are usually expressed in multiple cell types of a developing nervous system, yet their function is often only studied in specific cellular contexts
The availability of landmark strains for individual neuron types, the novel NeuroPAL landmark strain that allows for disambiguation of all 118 neuron classes (Yemini et al, 2021), allowed us to determine the complete pattern of unc-42 expression during larval development and adulthood
Most transcription factors are employed in distinct cell types to exert distinct, cell type-specific functions. unc-42 is an example of a relatively widely expressed transcription factor, operating in 15 distinct neuron classes of C. elegans
Summary
Individual gene regulatory factors are usually expressed in multiple cell types of a developing nervous system, yet their function is often only studied in specific cellular contexts. Many examples illustrate this regional bias in understanding gene function. The function of the mouse Brn3a POU homeobox gene has been extensively studied in some parts of the central nervous system, such as retinal ganglion cells, habenula, or peripheral sensory organs, but Brn3a function remains largely unexplored in other regions where the gene is expressed, including the interpeduncular nucleus or the superior colliculus (reviewed in Leyva-Dıaz et al, 2020).
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