Regulatory architecture controlling terminal differentiation of an interoceptive paraneuron in Caenorhabditis elegans

Interoceptive paraneurons are neuron-like cells located within internal epithelial cell surfaces that sense internal stimuli to evoke specific behavioral or physiological responses. The elucidation of terminal differentiation programs of paraneurons is expected to provide insights into how epithelial cells acquire neuron-like features during development and possibly also over evolutionary time. We define here the transcriptional programs that control the terminal differentiation of an interoceptive paraneuron class in the nematode Caenorhabditis elegans, called uv1. We show that, as in canonical neurons, the neuron-like secretory features of uv1 are controlled by a combination of CUT homeobox genes, while the combinatorial terminal gene battery that defines the unique functional features of uv1 is jointly controlled by a combination of at least three transcription factors: a LIM homeodomain (LIN-11), a SoxD (EGL-13) and a Pax (EGL-38) family protein. These factors act in a terminal selector-type manner to jointly co-regulate the many distinct uv1-paraneuron specific molecular features, such as sensory and neuromodulatory receptors, neuropeptides, and tyramine synthesis machinery. Our findings demonstrate notable similarities in the dichotomous architecture of gene regulatory programs of neurons and paraneurons.