Biology subjects

Singhvi, A.

Publications and source records attributed to Singhvi, A..

4 recordsLinked to original sources

bioRxiv2023

Molecular heterogeneity of C. elegans glia across sexes

A comprehensive description of nervous system function, and sex dimorphism within, is incomplete without clear assessment of the diversity of its component cell types, neurons and glia. C. elegans has an invariant nervous system with the first mapped connectome of a multi- cellular organism and single-cell atlas of component neurons. Here we present single nuclear RNA-seq evaluation of glia across the entire adult C. elegans nervous system, including both sexes. Machine learning models enabled us to identify both sex-shared and sex-specific glia and glial subclasses. We have identified and validated molecular markers in silico and in vivo for these molecular subcategories. Comparative analytics also reveals previously unappreciated molecular heterogeneity in anatomically identical glia between and within sexes, indicating consequent functional heterogeneity. Furthermore, our datasets reveal that while adult C. elegans glia express neuropeptide genes, they lack the canonical unc-31/CAPS-dependent dense core vesicle release machinery. Thus, glia employ alternate neuromodulator processing mechanisms. Overall, this molecular atlas, available at www.wormglia.org, reveals rich insights into heterogeneity and sex dimorphism in glia across the entire nervous system of an adult animal.

neuroscience↗

bioRxiv2023

Neuron cilia constrain glial regulators to microdomains around distal neurons

Each glia interacts with multiple neurons, but the fundamental logic of whether it interacts with all equally remains unclear. We find that a single sense-organ glia modulates different contacting neurons distinctly. To do so, it partitions regulatory cues into molecular microdomains at specific neuron contact-sites, at its delimited apical membrane. For one glial cue, K/Cl transporter KCC-3, microdomain-localization occurs through a two-step, neuron-dependent process. First, KCC-3 shuttles to glial apical membranes. Second, some contacting neuron cilia repel it, rendering it microdomain-localized around one distal neuron-ending. KCC-3 localization tracks animal aging, and while apical localization is sufficient for contacting neuron function, microdomain-restriction is required for distal neuron properties. Finally, we find the glia regulates its microdomains largely independently. Together, this uncovers that glia modulate cross-modal sensor processing by compartmentalizing regulatory cues into microdomains. Glia across species contact multiple neurons and localize disease-relevant cues like KCC-3. Thus, analogous compartmentalization may broadly drive how glia regulate information processing across neural circuits.

neuroscience↗

bioRxiv2022

Epithelia delimits glial apical polarity against mechanical shear to maintain glia-neuron architecture

For an organ to maintain proper architecture and function, its different component cell-types must coordinate their cell-shapes with each other through life. While cell-intrinsic developmental mechanisms driving homotypic cell-cell coordination are known, how heterotypic cells collectively regulate cell-shape is less-clear. We report that, in a sense-organ, epithelial cells delimit and maintain polarity domains of contacting glia, and thereby, associated neuron shapes throughout life. Briefly, Hsp co-chaperone UNC-23/BAG2 keeps epithelial apical domains from deforming with animal movement. Epithelial apical domains stretch aberrantly and progressively in adult unc-23 mutant animals, which in an FGFR-dependent manner, dislocates glial apical cytoskeleton proteins SMA-1/{beta}H-Spectrin and actin. This alters glial apical polarity and cell shape, and concomitantly, associated neuron-ending shape. Notably, UNC-23 acts temporally at a developmental critical period to maintain glia-neuron shape in adults, and spatially within a defined anatomical zone. Lastly, intervention in either epithelia, glia or neuron ameliorate or phenocopy unc-23 neural defects. Epi/endothelia resist mechanical stress and contact glia-neuron units across central/peripheral nervous systems and species, and all components of the identified molecular pathway are conserved and disease-relevant. Thus, we posit that analogous epithelia-glia mechanobiological coupling may broadly regulate glia-neuron shapes through animal life.

neuroscience↗

bioRxiv2020

Glia actively sculpt sensory neurons by controlled phagocytosis to tune animal behavior

Glia in the central nervous system engulf neuron fragments during synapse remodeling and recycling of photoreceptor outer-segments. Whether glia passively clear shed neuronal debris, or actively remove neuron fragments is unknown. How pruning of single-neuron endings impacts animal behavior is also unclear. Here we report that adult C. elegans AMsh glia engulf sensory endings of the AFD thermosensory neuron. Engulfment is regulated by temperature, AFDs sensory input, and tracks AFD activity. Phosphatidylserine (PS) flippase TAT-1/ATP8A, functions with glial PS-receptor PSR-1/PSR and PAT-2/-integrin to initiate engulfment. Glial CED-10/Rac1 GTPase, acting through a conserved GEF complex, executes phagocytosis using the actin-remodeler WSP-1/nWASp and the membrane-sealing factor EFF-1 fusogen. CED-10 levels determine engulfment rates, and engulfment-defective mutants exhibit altered AFD-ending shape and thermosensory behavior. Our findings reveal a molecular pathway underpinning glia-dependent phagocytosis in a peripheral sense-organ, and demonstrate that glia actively engulf neuron-fragments, with profound consequences on neuron shape and animal behavior.

neuroscience↗