Verina H Leung

All Publications

• Mapping cellular targets of covalent cancer drugs in the entire mammalian body. Cell Pang, Z., Leung, V. H., Wang, C. C., Attarpour, A., Rinaldi, A., Shen, H., Moya-Garzon, M. D., Sigua, L. H., Rammel, C., Selke, A., Glynn, C., Yender, M., Xu, S., Moslehi, J. J., Wu, P., Long, J. Z., Goubran, M., Cravatt, B. F., Ye, L. 2025

  Abstract

  As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the three-dimensional (3D) mammalian body. With simple and passive incubation steps, vCATCH offers cellular-resolution drug imaging in the entire adult mouse. We combined vCATCH with hydrogel-based reinforcement of three-dimensional imaging solvent-cleared organs (HYBRiD) imaging and virtual reality to visualize and quantify in vivo targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell-type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.

  View details for DOI 10.1016/j.cell.2025.11.030

  View details for PubMedID 41435821

• PIEZO channels link mechanical forces to uterine contractions in parturition. Science (New York, N.Y.) Zhang, Y., Kini, S. A., Mishkanian, S. A., Yarishkin, O., Luo, R., Seradj, S. H., Leung, V. H., Wang, Y., Servín-Vences, M. R., Keenan, W. T., Sonmez, U., Sanchez-Alavez, M., Liu, Y., Jin, X., Lipomi, D. J., Ye, L., Petrascheck, M., Frolova, A. I., England, S. K., Patapoutian, A. 2025; 390 (6774): eady3045

  Abstract

  Mechanical forces are extensively involved in pregnancy and parturition, but their precise roles and mechanisms remain poorly understood. We identified mechanically activated ion channels PIEZO1 and PIEZO2 as key mechanotransducers required for labor progression. Genetic deletion of Piezo1 and Piezo2 in mice resulted in weakened uterine contractions and severe parturition defects. Tissue-specific knockouts revealed that deletion in either uterus or sensory neurons alone caused modest defects whereas combined loss markedly impaired labor, demonstrating additive effects. Single-nuclei sequencing indicated that loss of PIEZO function reduced expression of connexin43 (Gja1), a gap junction protein in uterine smooth muscle cells, suggesting a mechanistic link to impaired contraction. These findings highlight the critical role of PIEZO channels in mechanotransduction during parturition and suggest therapeutic targets for labor dysfunction.

  View details for DOI 10.1126/science.ady3045

  View details for PubMedID 41231991

• A key role of PIEZO2 mechanosensitive ion channel in adipose sensory innervation. Cell metabolism Wang, Y., Zhang, Y., Leung, V. H., Seradj, S. H., Sonmez, U., Servin-Vences, M. R., Xiao, S., Ren, X., Wang, L., Mishkanian, S. A., Kini, S. A., Long, J. Z., Lipomi, D. J., Ye, L., Patapoutian, A. 2025

  Abstract

  Compared with the well-established functions of sympathetic innervation, the role of sensory afferents in adipose tissues remains less understood. Recent work has revealed the anatomical and physiological significance of adipose sensory innervation; however, its molecular underpinning remains unclear. Here, using organ-targeted single-cell RNA sequencing, we identified the mechanoreceptor PIEZO2 as one of the most prevalent receptors in fat-innervating dorsal root ganglia (DRG) neurons. PIEZO2 deletion in fat-innervating neurons induced transcriptional programs in adipose tissue resembling sympathetic activation, mirroring DRG ablation. Conversely, a gain-of-function PIEZO2 mutant shifted the adipose phenotypes in the opposite direction. These results indicate that PIEZO2 plays a major role in the sensory regulation of adipose tissues. This discovery opens new avenues for exploring mechanosensation in organs not traditionally considered mechanically active, such as adipose tissues, and therefore sheds light on the broader significance of mechanosensation in regulating organ function and homeostasis.

  View details for DOI 10.1016/j.cmet.2025.02.004

  View details for PubMedID 40054462

• Phosphorylation of pyruvate dehydrogenase inversely associates with neuronal activity. Neuron Yang, D., Wang, Y., Qi, T., Zhang, X., Shen, L., Ma, J., Pang, Z., Lal, N. K., McClatchy, D. B., Seradj, S. H., Leung, V. H., Wang, K., Xie, Y., Polli, F. S., Maximov, A., Gonzalez, O. C., de Lecea, L., Cline, H. T., Augustine, V., Yates, J. R., Ye, L. 2024

  Abstract

  For decades, the expression of immediate early genes (IEGs) such as FOS has been the most widely used molecular marker representing neuronal activation. However, to date, there is no equivalent surrogate available for the decrease of neuronal activity. Here, we developed an optogenetic-based biochemical screen in which population neural activities can be controlled by light with single action potential precision, followed by unbiased phosphoproteomic profiling. We identified that the phosphorylation of pyruvate dehydrogenase (pPDH) inversely correlated with the intensity of action potential firing in primary neurons. In in vivo mouse models, monoclonal antibody-based pPDH immunostaining detected activity decreases across the brain, which were induced by a wide range of factors including general anesthesia, chemogenetic inhibition, sensory experiences, and natural behaviors. Thus, as an inverse activity marker (IAM) in vivo, pPDH can be used together with IEGs or other cell-type markers to profile and identify bi-directional neural dynamics induced by experiences or behaviors.

  View details for DOI 10.1016/j.neuron.2023.12.015

  View details for PubMedID 38266644

• The role of somatosensory innervation of adipose tissues. Nature Wang, Y., Leung, V. H., Zhang, Y., Nudell, V. S., Loud, M., Servin-Vences, M. R., Yang, D., Wang, K., Moya-Garzon, M. D., Li, V. L., Long, J. Z., Patapoutian, A., Ye, L. 2022

  Abstract

  Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output1. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue2. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.

  View details for DOI 10.1038/s41586-022-05137-7

  View details for PubMedID 36045288