Jacqueline Bendrick

All Publications

• Engrafted nitrergic neurons derived from hPSCs improve gut dysmotility in mice. Nature Majd, H., Samuel, R. M., Cesiulis, A., Ramirez, J. T., Kalantari, A., Barber, K., Farahvashi, S., Ghazizadeh, Z., Majd, A., Chemel, A. K., Richter, M. N., Das, S., Bendrick, J. L., Keefe, M. G., Wang, J., Shiv, R. K., Bhat, S., Khoroshkin, M., Yu, J., Nowakowski, T. J., Wen, K. W., Goodarzi, H., Thapar, N., Kaltschmidt, J. A., McCann, C. J., Fattahi, F. 2025

  Abstract

  Gastrointestinal (GI) motility disorders represent a major medical challenge, with few effective therapies available. These disorders often result from dysfunction of inhibitory nitric oxide (NO)-producing motor neurons in the enteric nervous system, which are essential for regulating gut motility. Loss or dysfunction of NO neurons is linked to severe conditions, including achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation1,2. Here we introduce a platform based on human pluripotent stem cells (hPSCs) for therapeutic development targeting GI motility disorders. Using an unbiased screen, we identified drug candidates that modulate NO neuron activity and enhance motility in mouse colonic tissue ex vivo. We established a high-throughput strategy to define developmental programs driving the specification of NO neurons and found that inhibition of platelet-derived growth factor receptors (PDGFRs) promotes their differentiation from precursors of the enteric nervous system. Transplantation of these neurons into NO-neuron-deficient mice led to robust engraftment and improved GI motility, offering a promising cell-based therapy for neurodegenerative GI disorders. These studies provide a new framework for understanding and treating enteric neuropathies.

  View details for DOI 10.1038/s41586-025-09208-3

  View details for PubMedID 40562934

  View details for PubMedCentralID 4819870

• Enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Neuron Hunker, A. C., Wirthlin, M. E., Gill, G., Johansen, N. J., Hooper, M., Omstead, V., Vargas, S., Lerma, M. N., Taskin, N., Weed, N., Laird, W. D., Bishaw, Y. M., Bendrick, J. L., Gore, B. B., Ben-Simon, Y., Opitz-Araya, X., Martinez, R. A., Way, S. W., Thyagarajan, B., Otto, S., Sanchez, R. E., Alexander, J. R., Amaya, A., Amster, A., Arbuckle, J., Ayala, A., Baker, P. M., Barcelli, T., Barta, S., Bertagnolli, D., Bielstein, C., Bishwakarma, P., Bowlus, J., Boyer, G., Brouner, K., Casian, B., Casper, T., Chakka, A. B., Chakrabarty, R., Chong, P., Clark, M., Colbert, K., Daniel, S., Dawe, T., Departee, M., DiValentin, P., Donadio, N. P., Dotson, N. I., Dwivedi, D., Egdorf, T., Fliss, T., Gary, A., Goldy, J., Grasso, C., Groce, E. L., Gudsnuk, K., Han, W., Haradon, Z., Hastings, S., Helback, O., Ho, W. V., Huang, C., Johnson, T., Jones, D. L., Juneau, Z., Kenney, J., Leibly, M., Li, S., Liang, E., Loeffler, H., Lusk, N. A., Madigan, Z., Malloy, J., Malone, J., McCue, R., Melchor, J., Mich, J. K., Moosman, S., Morin, E., Naidoo, R., Newman, D., Ngo, K., Nguyen, K., Oster, A. L., Ouellette, B., Oyama, A. A., Pena, N., Pham, T., Phillips, E., Pom, C., Potekhina, L., Ransford, S., Ray, P. L., Reding, M., Rette, D. F., Reynoldson, C., Rimorin, C., Sigler, A. R., Rocha, D. B., Ronellenfitch, K., Ruiz, A., Sawyer, L., Sevigny, J. P., Shapovalova, N. V., Shepard, N., Shulga, L., Soliman, S., Staats, B., Taormina, M. J., Tieu, M., Wang, Y., Wilkes, J., Wood, T., Zhou, T., Williford, A., Dee, N., Mollenkopf, T., Ng, L., Esposito, L., Kalmbach, B. E., Yao, S., Ariza, J., Collman, F., Mufti, S., Smith, K., Waters, J., Ersing, I., Patrick, M., Zeng, H., Lein, E. S., Kojima, Y., Horwitz, G., Owen, S. F., Levi, B. P., Daigle, T. L., Tasic, B., Bakken, T. E., Ting, J. T. 2025; 113 (10): 1507

  Abstract

  We present an enhancer-AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct- and indirect-pathway MSNs, Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, by three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell-type-specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rats and macaques. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.

  View details for DOI 10.1016/j.neuron.2025.04.035

  View details for PubMedID 40403704

• Enhancer AAV Toolbox for Accessing and Perturbing Striatal Cell Types and Circuits Hunker, A., Wirthlin, M., Gill, G., Johansen, N., Hooper, M., Omstead, V., Taskin, N., Weed, N., Vargas, S., Bendrick, J., Gore, B., Ben-Simon, Y., Bishaw, Y., Opitz-Araya, X., Martinez, R., Way, S., Thyagarajan, B., Lerma, M., Laird, W., Otto, S., Sanchez, R., Kojima, Y., Horwitz, G., Owen, S., Levi, B., Daigle, T., Tasic, B., Bakken, T., Ting, J. CELL PRESS. 2025

  View details for Web of Science ID 001493880500125

• Enteric glutamatergic interneurons regulate intestinal motility. Neuron Hamnett, R., Bendrick, J. L., Saha, Z., Robertson, K., Lewis, C. M., Marciano, J. H., Zhao, E. T., Kaltschmidt, J. A. 2025

  Abstract

  The enteric nervous system (ENS) controls digestion autonomously via a complex neural network within the gut wall. Enteric neurons expressing glutamate have been identified by transcriptomic studies as a distinct subpopulation, and glutamate can affect intestinal motility by modulating enteric neuron activity. However, the nature of glutamatergic neurons, their position within the ENS circuit, and their function in regulating gut motility are unknown. We identify glutamatergic neurons as longitudinally projecting descending interneurons in the small intestine and colon and as a novel class of circumferential neurons only in the colon. Both populations make synaptic contact with diverse neuronal subtypes and signal with multiple neurotransmitters and neuropeptides in addition to glutamate, including acetylcholine and enkephalin. Knocking out the glutamate transporter VGLUT2 from enkephalin neurons disrupts gastrointestinal transit, while ex vivo optogenetic stimulation of glutamatergic neurons initiates colonic propulsive motility. Our results posit glutamatergic neurons as key interneurons that regulate intestinal motility.

  View details for DOI 10.1016/j.neuron.2025.01.014

  View details for PubMedID 39983724

• Enhancer viruses for combinatorial cell-subclass-specific labeling NEURON Graybuck, L. T., Daigle, T. L., Sedeno-Cortes, A. E., Walker, M., Kalmbach, B., Lenz, G. H., Morin, E., Thuc Nghi Nguyen, Garren, E., Bendrick, J. L., Kim, T., Zhou, T., Mortrud, M., Yao, S., Siverts, L., Larsen, R., Gore, B. B., Szelenyi, E. R., Trader, C., Balaram, P., van Velthoven, C. T. J., Chiang, M., Mich, J. K., Dee, N., Goldy, J., Cetin, A. H., Smith, K., Way, S. W., Esposito, L., Yao, Z., Gradinaru, V., Sunkin, S. M., Lein, E., Levi, B. P., Ting, J. T., Zeng, H., Tasic, B. 2021; 109 (9): 1449-+

  Abstract

  Rapid cell type identification by new genomic single-cell analysis methods has not been met with efficient experimental access to these cell types. To facilitate access to specific neural populations in mouse cortex, we collected chromatin accessibility data from individual cells and identified enhancers specific for cell subclasses and types. When cloned into recombinant adeno-associated viruses (AAVs) and delivered to the brain, these enhancers drive transgene expression in specific cortical cell subclasses. We extensively characterized several enhancer AAVs to show that they label different projection neuron subclasses as well as a homologous neuron subclass in human cortical slices. We also show how coupling enhancer viruses expressing recombinases to a newly generated transgenic mouse, Ai213, enables strong labeling of three different neuronal classes/subclasses in the brain of a single transgenic animal. This approach combines unprecedented flexibility with specificity for investigation of cell types in the mouse brain and beyond.

  View details for DOI 10.1016/j.neuron.2021.03.011

  View details for Web of Science ID 000694861200010

  View details for PubMedID 33789083

• Desmoplakin Harnesses Rho GTPase and p38 Mitogen-Activated Protein Kinase Signaling to Coordinate Cellular Migration. The Journal of investigative dermatology Bendrick, J. L., Eldredge, L. A., Williams, E. I., Haight, N. B., Dubash, A. D. 2018; 139 (6): 1227-1236

  Abstract

  Desmoplakin (DP) is an obligate component of desmosomal cell-cell junctions that links the adhesion plaque to the cytoskeletal intermediate filament network. While a central role for DP in maintaining the structure and stability of the desmosome is well established, recent work has indicated that DP's functions may extend beyond cell-cell adhesion. In our study, we show that loss of DP results in a significant increase in cellular migration, as measured by scratch wound assays, Transwell migration assays, and invasion assays. Loss of DP causes dramatic changes in actin cytoskeleton morphology, including enhanced protrusiveness, and an increase in filopodia length and number. Interestingly, these changes are also observed in single cells, indicating that control of actin morphology is a cell-cell adhesion-independent function of DP. An investigation of cellular signaling pathways uncovered aberrant Rac and p38 mitogen-activated protein kinase (MAPK) activity in DP knockdown cells, restoration of which is sufficient to rescue DP-dependent changes in both cell migration and actin cytoskeleton morphology. Taken together, these data highlight a previously uncharacterized role for the desmosomal cytolinker DP in coordinating cellular migration via p38 MAPK and Rac signaling.

  View details for DOI 10.1016/j.jid.2018.11.032

  View details for PubMedID 30579854

  View details for PubMedCentralID PMC6535125