The vagus nerve in cardiovascular physiology and pathophysiology: From evolutionary insights to clinical medicine.

The parasympathetic nervous system via the vagus nerve exerts profound influence over the heart. Together with the sympathetic nervous system, the parasympathetic nervous system is responsible for fine-tuned regulation of all aspects of cardiovascular function, including heart rate, rhythm, contractility, and blood pressure. In this review, we highlight vagal efferent and afferent innervation of the heart, with a focus on insights from comparative biology and advances in understanding the molecular and genetic diversity of vagal neurons, as well as interoception, parasympathetic dysfunction in heart disease, and the therapeutic potential of targeting the parasympathetic nervous system in cardiovascular disease.

Sensory neurons promote immune homeostasis in the lung.

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) and asthma. To explore tissue-specific functions, we inserted a human JAK1 GoF variant (JAK1GoF) into mice and observed the development of spontaneous AD-like skin disease but unexpected resistance to lung inflammation when JAK1GoF expression was restricted to the stroma. We identified a previously unrecognized role for JAK1 in vagal sensory neurons in suppressing airway inflammation. Additionally, expression of Calcb/CGRPß was dependent on JAK1 in the vagus nerve, and CGRPß suppressed group 2 innate lymphoid cell function and allergic airway inflammation. Our findings reveal evolutionarily conserved but distinct functions of JAK1 in sensory neurons across tissues. This biology raises the possibility that therapeutic JAK inhibitors may be further optimized for tissue-specific efficacy to enhance precision medicine in the future.

The unique function of Runx1 in skeletal muscle differentiation and regeneration is mediated by an ETS interaction domain.

The conserved Runt-related (RUNX) transcription factor family are well-known master regulators of developmental and regenerative processes. Runx1 and Runx2 are both expressed in satellite cells (SC) and skeletal myotubes. Conditional deletion of Runx1 in adult SC negatively impacted self-renewal and impaired skeletal muscle maintenance. Runx1- deficient SC retain Runx2 expression but cannot support muscle regeneration in response to injury. To determine the unique molecular functions of Runx1 that cannot be compensated by Runx2 we deleted Runx1 in C2C12 that retain Runx2 expression and established that myoblasts differentiation was blocked in vitro due in part to ectopic expression of Mef2c, a target repressed by Runx1 . Structure-function analysis demonstrated that the Ets-interacting MID/EID region of Runx1, absent from Runx2, is critical to regulating myoblasts proliferation, differentiation, and fusion. Analysis of in-house and published ChIP-seq datasets from Runx1 (T-cells, muscle) versus Runx2 (preosteoblasts) dependent tissue identified enrichment for a Ets:Runx composite site in Runx1 -dependent tissues. Comparing ATACseq datasets from WT and Runx1KO C2C12 cells showed that the Ets:Runx composite motif was enriched in peaks open exclusively in WT cells compared to peaks unique to Runx1KO cells. Thus, engagement of a set of targets by the RUNX1/ETS complex define the non-redundant functions of Runx1 .

"Goodnight" from the heart: A cardiovascular circuit that promotes sleep.

The baroreflex is essential for blood pressure homeostasis. In this issue of Neuron, Yao et al.1 uncover a novel role of brainstem barosensitive neurons in promoting non-REM (NREM) sleep, providing a direct link between the cardiovascular system and sleep-wake states.

Chromatin remodeler Znhit1 controls bone morphogenetic protein signaling in embryonic lung tissue branching.

Branching morphogenesis is a key process essential for lung and other organ development in which cellular and tissue architecture branch out to maximize surface area. While this process is known to be regulated by differential gene expression of ligands and receptors, how chromatin remodeling regulates this process remains unclear. Znhit1 (zinc finger HIT-type containing 1), acting as a chromatin remodeler, has previously been shown to control the deposition of the histone variant H2A.Z. Here, we demonstrate that Znhit1 also plays an important role in regulating lung branching. Using Znhit1 conditional KO mice, we show that Znhit1 deficiency in the embryonic lung epithelium leads to failure of branching morphogenesis and neonatal lethality, which is accompanied by reduced cell proliferation and increased cell apoptosis of the epithelium. The results from the transcriptome and the chromatin immunoprecipitation assay reveal that this is partially regulated by the derepression of Bmp4, encoding bone morphogenetic protein (BMP) 4, which is a direct target of H2A.Z. Furthermore, we show that inhibition of BMP signaling by the protein inhibitor Noggin rescues the lung branching defects of Znhit1 mutants ex vivo. Taken together, our study identifies the critical role of Znhit1/H2A.Z in embryonic lung morphogenesis via the regulation of BMP signaling.

A multidimensional coding architecture of the vagal interoceptive system.

Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival1-4. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers5,6. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.

Vagal sensory neurons and gut-brain signaling.

Our understanding of the gut system has been revolutionized over the past decade, in particular regarding its role in immune control and psychological regulation. The vagus nerve is a crucial link between gut and brain, transmitting diverse gut-derived signals, and has been implicated in many gastrointestinal, neurological, and immunological disorders. Using state-of-the-art technologies including single-cell genomic analysis, real-time neural activity recording, trans-synaptic tracing, and electron microscopy, novel physiological functions of vagal gut afferents have been uncovered, and new gut-to-brain pathways have been revealed. Here, we review the most recent findings on vagal sensory neurons and the gut-brain signaling, focusing on the anatomical basis and the underlying molecular and cellular mechanisms. Such new discoveries explain some of the old puzzling problems and also raise new questions in this exciting and rapidly growing field.

Pulmonary neuroendocrine cells amplify allergic asthma responses.

Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that Ascl1-mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in Ascl1-mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.