Biology subjects

Jaquish, A.

Publications and source records attributed to Jaquish, A..

5 recordsLinked to original sources

bioRxiv2025

Cell fate specification during respiratory development requires ARID1A-containing canonical BAF complex activity

Development of the mammalian lung requires formation of a definitive lung bud from the foregut endoderm, branching morphogenesis, specification of a proximal to distal axis, and differentiation of extensive specialized airway and alveolar epithelial lineages. These steps require coordinated temporal and regional gene expression to define the lung epithelium in preparation for the first breath at birth. While the transcriptional and signaling regulators required for lung development are increasingly well known, the key epigenetic complexes that interact with lineage transcription factors for cell-specific control of gene expression remain to be defined. Here, we identify a key role for the canonical BAF complex, an ATP-dependent chromatin remodeling complex, during lung epithelial development. Loss of canonical BAF activity throughout the foregut endoderm leads to complete failure of lung formation, and selective deletion of a single key subunit, ARID1A, leads to failure of proximal-distal axis specification, with dilated airway-like structures lined by ectopic basal cells found throughout the distal lung, and failure of specification of alveolar type 1 (AT1) cells in the distal saccular epithelium. In place of AT1 cells, we identified a highly proliferative epithelial cell state defined by joint activation of YAP and WNT signaling and loss of BMP signaling response, leading to increased proliferation and failure of appropriate epithelial differentiation. These changes resulted in secondary failure of mesenchymal and endothelial specification, leading to broad loss of patterning of the distal lung further disrupting peripheral lung morphogenesis. Using embryonic lung organoids, we demonstrate that exogenous BMP4 signaling is sufficient to rescue AT1 and AT2 cell differentiation in ARID1A-null epithelium, while WNT and YAP signaling require functional BAF complex. Together, these data demonstrate a requirement for the BAF complex for lung formation, proximal-distal patterning, and cell fate acquisition, and reveal surprising differential specificity between signaling pathways during lung development. One-Sentence SummaryFunctional BAF complex containing ARID1A is required for lung development.

developmental biology↗

bioRxiv2024

Expansion of mammary intraepithelial lymphocytes and intestinal inputs shape T cell dynamics in lactogenesis

Pregnancy brings about profound changes in the mammary gland to prepare for lactation, yet immunocyte changes that accompany this rapid remodeling are incompletely understood. We comprehensively analyzed mammary T cells, revealing a marked increase in CD4+ and CD8+ T effector cells, including an expansion of TCR{beta}+CD8+ cells, in pregnancy and lactation. T cells were localized in the mammary epithelium, resembling intraepithelial lymphocytes (IELs) typically found in mucosal tissues. Similarity to mucosal tissues was substantiated by demonstrating partial dependence on microbial cues, T cell migration from the intestine to the mammary gland in late pregnancy, and shared TCR clonotypes between intestinal and mammary tissues, including intriguing public TCR families. Putative counterparts of mammary IELs were found in human breast and milk. Mammary T cells are thus poised to manage the transition from a non-mucosal tissue to a mucosal barrier during lactogenesis.

immunology↗

bioRxiv2022

Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair

While the lung bears significant regenerative capacity, severe viral pneumonia can chronically impair lung function by triggering dysplastic remodeling. The connection between these enduring changes and chronic disease remains poorly understood. We recently described the emergence of tuft cells within Krt5+ dysplastic regions after influenza injury. Using bulk and single cell transcriptomics, we characterized and delineated multiple distinct tuft cell populations that arise following influenza clearance. Distinct from intestinal tuft cells which rely on Type 2 immune signals for their expansion, neither IL-25 nor IL-4R signaling are required to drive tuft cell development in dysplastic/injured lungs. Furthermore, tuft cells were also observed upon bleomycin injury, suggesting that their development may be a general response to severe lung injury. While intestinal tuft cells promote growth and differentiation of surrounding epithelial cells, in the lungs of tuft cell deficient mice, Krt5+ dysplasia still occurs, goblet cell production is unchanged, and there remains no appreciable contribution of Krt5+ cells into more regionally appropriate alveolar Type 2 cells. Together, these findings highlight unexpected differences in signals necessary for lung tuft cell amplification and establish a framework for future elucidation of tuft cell functions in pulmonary health and disease.

cell biology↗

bioRxiv2021

Mapping the Central and Peripheral Projections of Lung Innervating Sensory Neurons

While best known as the gas exchange organ, the lung is also critical for sensing and responding to the aerosol environment in part through interaction with the nervous system. The rich diversity of lung innervating neurons remains poorly understood. Here, we interrogated the cell body location, projection pattern and targets of lung-innervating sensory neurons. Retrograde tracing from the lung labeled neurons primarily in the vagal ganglia, in a spatially distributed population expressing markers including Vglut2, Trpv1, Tac1, Calb1 or Piezo2. Centrally, they project to the nucleus of the solitary tract in the brainstem. Peripherally, they project along the branching airways and terminate on airway smooth muscles, vasculature including lymphatics, and selected alveoli. Notably, a discrete population of Calb1+ neurons preferentially innervate pulmonary neuroendocrine cells, a demonstrated airway sensor population. This comprehensive illustration of the properties of lung innervating sensory neurons serves as a foundation for understanding their function in lung.

cell biology↗

bioRxiv2019

Vaping nicotine-containing electronic cigarettes produces addiction-like behaviors and cardiopulmonary abnormalities in rats

The debate about electronic cigarettes has divided healthcare professionals, policymakers, and communities. Central points of disagreement are whether vaping electronic cigarettes are addictive and whether they produce major pulmonary complications. We developed a novel model of nicotine vapor self-administration in rats and found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans, exhibiting both addiction-like behaviors and cardiopulmonary abnormalities. The smoking cessation drug varenicline decreased electronic cigarette self-administration. These findings confirm the addictive properties and harmful effects of nicotine vapor and identify a potential medication for the treatment of electronic cigarette addiction.\n\nOne Sentence SummaryVaping nicotine-containing electronic cigarettes produces cardiopulmonary abnormalities, nicotine dependence and addiction-like behaviors, which are reduced by the smoking cessation drug varenicline.

neuroscience↗