Biology subjects

Philbrook, A.

Publications and source records attributed to Philbrook, A..

6 recordsLinked to original sources

bioRxiv2026

Neuron-intrinsic and glial pathways regulate sensory cilia regeneration in adult C. elegans

Primary cilia are microtubule-based organelles that mediate cellular responses to environmental cues. Although cilia disassemble and reassemble upon cell cycle entry and exit, respectively, in dividing cells, it remains unclear whether postmitotic cells such as neurons can regenerate these structures in vivo following injury to restore function, and whether this process recapitulates developmental ciliogenesis. Here we show that a subset of sensory neuron cilia in adult C. elegans regrows following conditional truncation and restores neuronal functions. This regeneration is regulated by both cell-intrinsic and extrinsic mechanisms that are in part distinct from those employed during embryonic ciliogenesis. We find that the conserved ciliogenic DAF-19 RFX transcription factor is dispensable for cilia maintenance in the adult but is required for regeneration, in part via transcriptional upregulation of a subset of ciliary intraflagellar transport (IFT) genes. We further identify the DLK-1 dual leucine-zipper kinase and the CEBP-1 C/EBP transcription factor, previously implicated in axon regeneration, as necessary for efficient cilia regrowth but not for developmental ciliogenesis. We show that cebp-1 expression is induced during cilia truncation and regrowth and that this induction is also DAF-19-dependent. Finally, we show that cilia truncation and regeneration dynamics vary in a neuron type-specific manner and are modulated by signals from surrounding glia. Our results establish that the cilia of mature neurons can regenerate and recover functions in vivo and identify conserved pathways that regulate this process in adult animals.

cell biology↗

bioRxiv2025

A lateralized sensory signaling pathway mediates context-dependent olfactory plasticity in C. elegans

Lateralization of neuronal functions plays a critical role in regulating behavioral flexibility, but the underlying molecular mechanisms are challenging to establish at a single-neuron level. We previously showed that attraction of C. elegans to a medium-chain alcohol switches to avoidance in a uniform background of a second attractive odorant. This context-dependent behavioral plasticity is mediated by symmetric inversion of the odor-evoked response sign in the bilateral AWC olfactory neurons. Here we show that this symmetric response plasticity is driven by asymmetric molecular mechanisms in the AWC neuron pair. Mutations in the gcy-12 receptor guanylyl cyclase abolish odor response plasticity only in AWCOFF; the opposing odor-evoked response signs in AWCOFF and AWCON in gcy-12 mutants results in these animals being behaviorally indifferent to this chemical. We find that gcy-12 is expressed, and required, in both AWC neurons to regulate odor response plasticity only in AWCOFF. We further show that disruption of AWC fate lateralization results in loss of asymmetry in the response plasticity in gcy-12 mutants. Our results indicate that symmetric neuronal response plasticity can arise from asymmetry in underlying molecular mechanisms, and suggest that lateralization of signaling pathways in defined conditions may enhance neuronal and behavioral flexibility.

neuroscience↗

bioRxiv2024

Differential modulation of sensory response dynamics by cilia structure and intraflagellar transport within and across chemosensory neurons

Sensory neurons contain morphologically diverse primary cilia that are built by intraflagellar transport (IFT) and house sensory signaling molecules. Since both ciliary structural and signaling proteins are trafficked via IFT, it has been challenging to decouple the contributions of IFT and cilia structure to neuronal responses. By acutely inhibiting IFT without altering cilia structure and vice versa, here we describe the differential roles of ciliary trafficking and sensory ending morphology in shaping chemosensory responses in C. elegans. We show that a minimum cilium length but not continuous IFT is necessary for a subset of responses in the ASH nociceptive neurons. In contrast, neither cilia nor continuous IFT are necessary for odorant responses in the AWA olfactory neurons. Instead, continuous IFT differentially modulates response dynamics in AWA. Upon acute inhibition of IFT, cilia-destined odorant receptors are shunted to ectopic branches emanating from the cilia base. Spatial segregation of receptors in these branches from a cilia-restricted regulatory kinase results in odorant desensitization defects, highlighting the importance of precise organization of signaling molecules at sensory endings in regulating response dynamics. We also find that adaptation of AWA responses upon repeated exposure to an odorant is mediated by IFT-driven removal of its cognate receptor, whereas adaptation to a second odorant is regulated via IFT-independent mechanisms. Our results reveal unexpected complexity in the contribution of IFT and cilia organization to the regulation of responses even within a single chemosensory neuron type, and establish a critical role for these processes in the precise modulation of olfactory behaviors.

neuroscience↗

bioRxiv2022

Developmental history modulates adult olfactory behavioral preferences via regulation of chemoreceptor expression in C. elegans

Developmental experiences play critical roles in shaping adult physiology and behavior. We and others previously showed that adult C. elegans which transiently experienced dauer arrest during development (PD: post-dauer) exhibit distinct gene expression profiles as compared to control adults which bypassed the dauer stage. In particular, the expression patterns of subsets of chemoreceptor genes are markedly altered in PD adults. Whether altered chemoreceptor levels drive behavioral plasticity in PD adults is unknown. Here we show that PD adults exhibit enhanced attraction to a panel of food-related attractive volatile odorants including the bacterially-produced chemical diacetyl. Diacetyl-evoked responses in the AWA olfactory neuron pair are increased in both dauer larvae and PD adults, and we find that these increased responses are correlated with upregulation of the diacetyl receptor ODR-10 in AWA likely via both transcriptional and post-transcriptional mechanisms. We show that transcriptional upregulation of odr-10 expression in dauer larvae is in part mediated by the DAF-16 FOXO transcription factor. Via transcriptional profiling of sorted populations of AWA neurons from control and PD adults, we further show that the expression of a subset of additional chemoreceptor genes in AWA is regulated similarly to odr-10 in PD animals. Our results suggest that developmental experiences may be encoded at the level of olfactory receptor regulation, and provide a simple mechanism by which C. elegans is able to precisely modulate its behavioral preferences as a function of its current and past experiences.

neuroscience↗

bioRxiv2021

Kinesin-3 mediated delivery of presynaptic neurexin stabilizes growing dendritic spines and postsynaptic components in vivo

The functional properties of neural circuits are defined by the patterns of synaptic connections between their partnering neurons, but the mechanisms that stabilize circuit connectivity are poorly understood. We systemically examined this question at synapses onto newly characterized dendritic spines of C. elegans GABAergic motor neurons. We show that the presynaptic adhesion protein, neurexin/NRX-1, is required for stabilization of postsynaptic structure. We find that early postsynaptic developmental events proceed without a strict requirement for synaptic activity and are not disrupted by deletion of neurexin/nrx-1. However, in the absence of presynaptic NRX-1, dendritic spines and receptor clusters become destabilized and collapse prior to adulthood. We demonstrate that kinesin-3/UNC-104 delivers NRX-1 to presynaptic terminals and show that ongoing delivery is required for postsynaptic maintenance in mature animals. By defining the dynamics and temporal order of synapse formation events in vivo, we describe a mechanism for stabilizing mature circuit connectivity through neurexin-based adhesion.

neuroscience↗

bioRxiv2019

The C. elegans Tubby homolog dynamically modulates olfactory cilia membrane morphogenesis and phospholipid composition

Plasticity in sensory signaling is partly mediated via regulated trafficking of signaling molecules to and from primary cilia. Tubby-related proteins regulate ciliary protein transport; however, their roles in remodeling of cilia properties are not fully understood. We find that the C. elegans TUB-1 Tubby homolog regulates membrane morphogenesis and signaling protein transport in specialized sensory cilia. In particular, TUB-1 is essential for sensory signaling-dependent reshaping of olfactory cilia morphology. We show that compromised sensory signaling alters cilia membrane phosphoinositide composition via TUB-1-dependent trafficking of a PIP5 kinase. TUB-1 regulates localization of this lipid kinase at the cilia base in part via localization of the AP-2 adaptor complex subunit DPY-23. Our results describe new functions for Tubby proteins in the dynamic regulation of cilia membrane lipid composition, morphology, and signaling protein content, and suggest that this conserved family of proteins plays a critical role in mediating cilia structural and functional plasticity.

cell biology↗