Every organ in the body is made up of a range of cell types that must coordinate their size and shape throughout the lifetime of the animal to maintain correct organ architecture and function. A focus of Dr. Aakanksha Singhvi and her team is how glia-neuron units in sense organs maintain their architecture and function. Sensory organs detect changes in the environment, cuing an organism to modify its behavior in response. They are typically made up of neurons, glia (non-neuronal support cells), and epithelial and endothelial cells. The formation of cell-cell junctions, created by intercellular protein-protein interactions, is one mechanism epithelial cells use to maintain their shape, relative orientation and carry out their barrier function. However, it is less well known if epithelia and other cell types in a sense-organ interact to coordinate their shape and function. In a recent paper in Developmental Cell, the Singhvi lab reported that epithelial cells require UNC-23/BAG2, an Hsp co-chaperone, to maintain their own shape, and also the shape of neighboring glia-neuron units in many sensory organs in C. elegans.
With a relatively simple nervous system of 302 neurons and 56 glia, the tiny worm C. elegans provides a tractable model to better understand how cell shape and sensory organ architecture regulates animal behavior and memory. The Singhvi lab previously examined how the amphid sheath (AMsh) glia regulate the primary thermosensory neuron, AFD, in worms. They found that AMsh glia actively sculpt the AFD neuron sensory endings by phagocytosis to tune animal behavior.
In their most recent work, they sought to identify other regulators of AFD sensory endings. “The science serendipitously led us to this exciting topic and finding, which I am now fascinated by,” says Dr. Singhvi. “It started when I uncovered a mutant from a genetic screen. It was one of six mutants I had found, and intriguing to me because it had the exact opposite phenotype from the rest. It was a cool mystery I just could not let slide.” The mutation was found to be in UNC-23, a heat shock protein co-chaperone and ortholog of human BAG2. unc-23 mutants displayed an AFD sensory ending overgrowth phenotype that they termed “meander”. While UNC-23 is broadly expressed in worms, they found that it was UNC-23 loss in epithelial cells and not the AMsh glia or AFD neurons that was causing the neuron-ending to meander when the animal felt mechanical stress from movement. Further, they also realized that UNC-23 loss affected many glia-neuron pairs, and all got worse as the animal aged. “Epithelia help glia-neuron units withstand mechanical stress lifelong. If they cannot, as in the mutant, it affects glia and neuron properties. Thus, our study reveals that non-neural epithelia are players in nervous system maintenance and aging through life,” says Dr. Singhvi.
Uncovering how this happens, the Singhvi lab showed that epithelial UNC-23 regulates SMA-1/βH-spectrin in glial cells via EGL-15/FGFR signaling. This epithelia-glia signaling is constrained in both space, affecting only glia-neuron pairs in the head of the animal (like AMsh glia/AFD), and time, during larval stage 4 into the adult worm. “So, not only do epithelia talk to glia, but do so with exquisite spatio-temporal complexity throughout the animal brain,” says Dr. Singhvi. “We are excited to follow this and to consider what we have found in the context of touch and pain sensation, aging, and brain cancer.”
The spotlighted research was funded by the National Institutes of Health, the Simons Foundation, the Esther A. & Joseph Klingenstein-Simons Fund, the Brain Research Foundation, the Glenn Foundation for Medical Research and the American Federation for Aging Research (AFAR), and philanthropic support.
Fred Hutch/University of Washington/Seattle Children's Cancer Consortium member Dr. Aakanksha Singhvi contributed to this work.
Martin CG, Bent JS, Hill T, Topalidou I, Singhvi A. 2024. Epithelial UNC-23 limits mechanical stress to maintain glia-neuron architecture in C. elegans. Dev. Cell. S1534-5807(24)00230-2.