Biology subjects

Wells, A. C.

Publications and source records attributed to Wells, A. C..

4 recordsLinked to original sources

bioRxiv2025

Basal cytoplasmic calcium levels regulate C. elegans germ stem cell proliferation

The C. elegans germline is one of the foremost model systems for the study of germ cell biology. We have created an integrated ratiometric calcium reporter that allows comparative analysis of calcium levels in germ cells. We observe a positive correlation between the rate of cell proliferation and calcium levels. Conditions that decrease proliferation decrease basal cytoplasmic calcium levels, these include starvation and loss of insulin, TGF-{beta}, and folate signaling. Conversely, overproliferating germline tumor cells have increased basal cytoplasmic calcium levels. To determine if basal calcium levels regulate the rate of proliferation, we decreased calcium levels by inactivating the TRPM7-related GON-2 calcium channel. A gon-2 null mutant has significantly decreased basal cytoplasmic calcium levels and germ cell proliferation. Partial reduction of GON-2 activity in a gon-2 mutant heterozygote also reduces calcium levels and proliferation, but to a lower extent. This identifies GON-2 as a calcium channel that is required to maintain basal cytoplasmic calcium levels in germ cells. Conversely, increasing basal cytoplasmic calcium levels in germ cells either by inhibiting the plasma membrane calcium ATPase (which transports cytoplasmic calcium out of cells) or by inhibiting the SERCA channel (which transports cytoplasmic calcium into the endoplasmic reticulum) increased basal calcium levels and germ cell proliferation. This study identifies the germ line as the first tissue in C. elegans whose rate of cell proliferation is regulated by calcium. While transient increases in calcium are associated with cell proliferation in many animal species, our study suggests that the basal level of cytoplasmic calcium acts as a rheostat to modulate the rate of C. elegans germ cell proliferation in response to physiological processes and signals.

developmental biology↗

bioRxiv2024

Adaptive immunity to retroelements promotes barrier integrity

Maintenance of tissue integrity is a requirement of host survival. This mandate is of prime importance at barrier sites that are constitutively exposed to the environment. Here, we show that exposure of the skin to non-inflammatory xenobiotics promotes tissue repair; more specifically, mild detergent exposure promotes the reactivation of defined retroelements leading to the induction of retroelement-specific CD8+ T cells. These T cell responses are Langerhans cell dependent and establish tissue residency within the skin. Upon injury, retroelement-specific CD8+ T cells significantly accelerate wound repair via IL-17A. Collectively, this work demonstrates that tonic environmental exposures and associated adaptive responses to retroelements can be coopted to preemptively set the tissue for maximal resilience to injury.

immunology↗

bioRxiv2023

The neuroimmune CGRP-RAMP1 axis tunes cutaneous adaptive immunity to the microbiota

The somatosensory nervous system surveils external stimuli at barrier tissues, regulating innate immune cells under infection and inflammation. The roles of sensory neurons in controlling the adaptive immune system, and more specifically immunity to the microbiota, however, remain elusive. Here, we identified a novel mechanism for direct neuroimmune communication between commensal-specific T lymphocytes and somatosensory neurons mediated by the neuropeptide Calcitonin Gene-Related Peptide (CGRP) in the skin. Intravital imaging revealed that commensal-specific T cells are in close proximity to cutaneous nerve fibers in vivo. Correspondingly, we observed upregulation of the receptor for the neuropeptide CGRP, RAMP1, in CD8+ T lymphocytes induced by skin commensal colonization. Neuroimmune CGRP-RAMP1 signaling axis functions in commensal-specific T cells to constrain Type 17 responses and moderate the activation status of microbiota-reactive lymphocytes at homeostasis. As such, modulation of neuroimmune CGRP-RAMP1 signaling in commensal-specific T cells shapes the overall activation status of the skin epithelium, thereby impacting the outcome of responses to insults such as wounding. The ability of somatosensory neurons to control adaptive immunity to the microbiota via the CGRP-RAMP1 axis underscores the various layers of regulation and multisystem coordination required for optimal microbiota-reactive T cell functions under steady state and pathology. Significance statementMultisystem coordination at barrier surfaces is critical for optimal tissue functions and integrity, in response to microbial and environmental cues. In this study, we identified a novel neuroimmune crosstalk mechanism between the sensory nervous system and the adaptive immune response to the microbiota, mediated by the neuropeptide CGRP and its receptor RAMP1 on skin microbiota-induced T lymphocytes. The neuroimmune CGPR-RAMP1 axis constrains adaptive immunity to the microbiota and overall limits the activation status of the skin epithelium, impacting tissue responses to wounding. Our study opens the door to a new avenue to modulate adaptive immunity to the microbiota utilizing neuromodulators, allowing for a more integrative and tailored approach to harnessing microbiota-induced T cells to promote barrier tissue protection and repair.

immunology↗

bioRxiv2018

Identification of essential regulatory elements in the human genome

The identification of essential regulatory elements is central to the understanding of the consequences of genetic variation. Here we use novel genomic data and machine learning techniques to map essential regulatory elements and to guide functional validation. We train an XGBoost model using 38 functional and structural features, including genome essentiality metrics, 3D genome organization and enhancer reporter STARR-seq data to differentiate between pathogenic and control non-coding genetic variants. We validate the accuracy of prediction by using data from tiling-deletion-based and CRISPR interference screens of activity of cis-regulatory elements. In neurodevelopmental disorders, the model (ncER, non-coding Essential Regulation) maps essential genomic segments within deletions and rearranged topologically associated domains linked to human disease. We show that the approach successfully identifies essential regulatory elements in the human genome.

genomics↗