Joshua D Wythe

Associate Professor, Cell and Developmental Biology

Primary Location

3007 Pinn Hall
PO Box 800732

Website

https://www.wythelab.com/

Bio & Overview

The cardiovascular system is the first organ system to form in vertebrates and it is essential for embryonic survival. This system continually grows and remodels to meet the increasing energetic demands of the fetus, and it is also essential for maintaining adult homeostasis. Identifying the networks controlling blood vessel and cardiac morphogenesis, and the pathways maintaining their function in adults, are critical for elucidating the mechanisms underlying congenital birth defects, as well as for developing therapeutics to combat cardiovascular disease: the leading cause of mortality and morbidity in the world. The main focus of our research is to understand the molecular, genetic, and cellular mechanisms underpinning the formation, function, and maintenance of blood vessels in the developing vertebrate embryo, while simultaneously understanding how these factors are dysregulated in pathological settings in the adult, with a focus on diseases that impact the brain, such as stroke, vascular dementia, and brain cancer. We combine both zebrafish and mouse genetic models together with bioinformatics, functional genomics, and 3D imaging to investigate blood vessel development and pathogenesis. We are currently pursuing three main projects in our laboratory, among others: 1) Defining the transcriptional basis of endothelial plasticity and function. Vessels of different organs have unique properties, such as the impermeable nature of the brain endothelium (e.g. the blood brain barrier or BBB) versus the porous, fenestrated endothelium of the liver. The basis for this heterogeneity is unknown. Through bulk and single cell transcriptional and epigenetic (ATAC-seq) profiling and informatic analyses we have identified a set of core transcription factors unique the vessels of each major organ. We are now focusing on the transcription factors that govern BBB acquisition, and determining if these same factors can reprogram the functional characteristics of vessels in other organs to make them adopt different functional properties and characteristics. 2) The role of RAS/MEK/ERK signaling in brain arteriovenous malformations. We recently found that endothelial-specific gain of function mutations in KRAS are present in brain arteriovenous malformations: shunts or abnormal connections between arteries and veins that lack an intervening capillary network. These shunts are fragile and prone to rupture, which leads to intracerebral hemorrhage and possibly death. We are now asking if targeting this pathway can block or reverse these lesions, while also pursuing the mechanisms of KRAS-induced bAVMs at the cellular and molecular level. 3) Identifying novel therapeutic vulnerabilities in glioblastoma. Excessive endothelial cell proliferation and sprouting are defining features of the deadly adult brain cancer, glioblastoma multiforme (GBM). Our work has demonstrated that blood vessels in GBM display structural and functional heterogeneity. Currently, we determining if developmental angiogenic regulators we’ve identified also regulate pathogenic angiogenesis in this setting, and whether these factors can be targeted to inhibit tumor vascularization, and thus disease progression. Other projects include modelling vascular dementia in mice, creating novel animal models of lymphatic vessel malformations in mice and zebrafish, and creating novel animal models of inherited and sporadic diseases that feature cardiovascular defects. At the heart of these projects is a concerted effort to identity the transcriptional regulators and molecular networks that endow endothelium with their unique functional characteristics (such as impressive barrier function of the BBB in the brain). To achieve this goal requires a detailed mechanistic understanding of how endothelial cell identity is specified and maintained and the long-term objective of our research is to gain a deeper understanding of these mechanisms to facilitate the repair or replacement of damaged or dysfunctional vessels, or alternatively prevent exuberant vascularization in disease settings, such as glioma.

Academic Information

Department: Cell and Developmental Biology

Primary Education

BA, History, Miami University, 2001
BS, Botany, Miami University, 2001
PhD, Oncological Sciences / Cardiovascular Development, University of Utah School of Medicine, 2007
Postdoctoral Fellowship, Cardiovascular Development and Disease, University of California, San Francisco, 2014

Other Affiliations

MSTP

Research Interests

Cardiovascular Development and Cerebrovascular Pathologies

Research Disciplines

Cancer Biology
Cardiovascular Biology
Cell and Developmental Biology
Development, Stem Cells & Regeneration
Genetics
Neuroscience
Translational Science

Research Opportunities

Bioinformatics & Genomics
Cancer Biology
Cardiovascular Disease
Cell Biology
Development, Stem Cells & Regeneration
Genetics
Neuroscience

PhD Programs

Cell Biology
Neuroscience

Selected Publications

2025

Cantu Gutierrez ME, Hill MC, Largoza GE, Gillespie WB 3rd, Martin JF, Wythe JD. (2025) Mapping the transcriptional and epigenetic landscape of organotypic endothelial diversity in the developing and adult mouse. Nat Cardiovasc Res. doi: 10.1038/s44161-025-00618-0

Ricciardelli AR, Genet G, Genet N, McClugage ST 3rd, Kan PT, Hirschi KK, Fish JE, Wythe JD. (2025) From bench to bedside: murine models of inherited and sporadic brain arteriovenous malformations. Angiogenesis. doi:10.1007/s10456-024-09953-5

Kim GS, Harmon E, Gutierrez MC, Kim S, Vance L, Burrous H, Stephenson JM, Chauhan A, Banerjee A, Wise Z, Doan A, Ahn J, Wu T, Bautista-Garrido J, Lee J, Tan C, Jung JE, McCullough LD, Wythe JD, Marrelli SP. (2025) Single-cell analysis identifies Ifi27l2a as a gene regulator of microglial inflammation in the context of aging and stroke in mice. Nat Commun. doi: 10.1038/s41467-025-56847-1

Gladwell RA, Fisher DG, Wythe JD, Highley CB, Lukens JR, Price RJ. (2025) Computational Fluid Dynamic Model Prediction of Enhanced Glymphatic Clearance in Response to Focused Ultrasound-Mediated Blood-Brain Barrier Opening. Adv Sci (Weinh). doi: 10.1002/advs.202510684

Younis J, Ahn T, Tovias L, Ishola AO, Leynes C, Kirk JM, Perry SK, Gandhi A; RE-JOIN Consortium; Emrick JJ, Lee BH, Wythe JD, Haelterman NA. (2025) KneEZ Clear, an Effective Tissue Clearing Protocol to Study Musculoskeletal Tissues in the Mouse. bioRxiv [Preprint]. doi: 10.1101/2025.08.13.670136

Ishola AO, Pillai A, Ahn T; RE-JOIN Consortium; Hsu CW, Lee B, Haelterman N, Wythe JD. (2025) Optimization of Tissue Clearing Methods and Imaging Conditions for 3D Visualization of the Vasculature of the Adult Murine Knee. bioRxiv [Preprint]. doi: 10.1101/2025.06.26.661802

2024

Gillespie, W., Zhang, Y., Ruiz, O. E., Cerda, J., Ortiz-Guzman, J., Turner, W. D., . . . Wythe, J. D. (2024). Multisite Assembly of Gateway Induced Clones (MAGIC): a flexible cloning toolbox with diverse applications in vertebrate model systems.. bioRxiv. doi:10.1101/2024.07.13.603267

Suarez, C. F., Harb, O. A., Robledo, A., Largoza, G., Ahn, J. J., Alley, E. K., . . . Wythe, J. D. (2024). MEK signaling represents a viable therapeutic vulnerability of KRAS-driven somatic brain arteriovenous malformations.. bioRxiv. doi:10.1101/2024.05.15.594335

Ahn, T., Largoza, G. E., Younis, J., Dickinson, M. E., Hsu, C. -W., & Wythe, J. D. (2024). Protocol for optical, aqueous-based clearing of murine tissues using EZ Clear. STAR PROTOCOLS, 5(2). doi:10.1016/j.xpro.2024.103053

2023

Long, H., Steimle, J., Canozo, F. J. G., Kim, J. H., Li, X., Morikawa, Y., . . . Martin, J. F. (2024). Endothelial cells adopt a pro-reparative immune responsive signature during cardiac injury. LIFE SCIENCE ALLIANCE, 7(2). doi:10.26508/lsa.202201870

Ricciardelli, A. R., Robledo, A., Fish, J. E., Kan, P. T., Harris, T. H., & Wythe, J. D. (2023). The Role and Therapeutic Implications of Inflammation in the Pathogenesis of Brain Arteriovenous Malformations. BIOMEDICINES, 11(11). doi:10.3390/biomedicines11112876

Kim, G. S., Harmon, E., Gutierrez, M., Stephenson, J., Chauhan, A., Banerjee, A., . . . Marrelli, S. (2023). Single-cell analysis identifies Ifi27l2a as a novel gene regulator of microglial inflammation in the context of aging and stroke.. Res Sq. doi:10.21203/rs.3.rs-2557290/v1

2022

Hsu, C. -W., Cerda, J., Kirk, J. M., Turner, W. D., Rasmussen, T. L., Suarez, C. P. F., . . . Wythe, J. D. (2022). EZ Clear for simple, rapid, and robust mouse whole organ clearing. ELIFE, 11. doi:10.7554/eLife.77419

Soon, K., Li, M., Wu, R., Zhou, A., Khosraviani, N., Turner, W. D., . . . Nunes, S. S. (2022). A human model of arteriovenous malformation (AVM)-on-a-chip reproduces key disease hallmarks and enables drug testing in perfused human vessel networks. BIOMATERIALS, 288. doi:10.1016/j.biomaterials.2022.121729

Mayerich, D., & Wythe, J. D. (2022). Computational insights on coronary artery function. NATURE CARDIOVASCULAR RESEARCH, 1(8), 691-693. doi:10.1038/s44161-022-00115-8

Li-Villarreal, N., Wong, R. L. Y., Garcia, M. D., Udan, R. S., Poche, R. A., Rasmussen, T. L., . . . Dickinson, M. E. (2022). FOXO1 represses sprouty 2 and sprouty 4 expression to promote arterial specification and vascular remodeling in the mouse yolk sac. DEVELOPMENT, 149(7). doi:10.1242/dev.200131

Verma, S. K., Deshmukh, V., Thatcher, K., Belanger, K. K., Rhyner, A. M., Meng, S., . . . Kuyumcu-Martinez, M. N. (2022). RBFOX2 is required for establishing RNA regulatory networks essential for heart development. NUCLEIC ACIDS RESEARCH, 50(4), 2270-2286. doi:10.1093/nar/gkac055

2021

Rohde, D., Vandoorne, K., Lee, I. -H., Grune, J., Zhang, S., McAlpine, C. S., . . . Nahrendorf, M. (2022). Bone marrow endothelial dysfunction promotes myeloid cell expansion in cardiovascular disease. NATURE CARDIOVASCULAR RESEARCH, 1(1), 28-+. doi:10.1038/s44161-021-00002-8

Shao, Y., Bajikar, S. S., Tirumala, H. P., Gutierrez, M. C., Wythe, J. D., & Zoghbi, H. Y. (2021). Identification and characterization of conserved noncoding cis-regulatory elements that impact Mecp2 expression and neurological functions. GENES & DEVELOPMENT, 35(7-8), 489-494. doi:10.1101/gad.345397.120

2020

Carlson, J. C., Gutierrez, M. C., Lozzi, B., Huang-Hobbs, E., Turner, W. D., Tepe, B., . . . Deneen, B. (2021). Identification of diverse tumor endothelial cell populations in malignant glioma. NEURO-ONCOLOGY, 23(6), 932-944. doi:10.1093/neuonc/noaa297

Geng, X., Yanagida, K., Akwii, R. G., Choi, D., Chen, L., Ho, Y., . . . Srinivasan, R. S. (2020). S1PR1 regulates the quiescence of lymphatic vessels by inhibiting laminar shear stress-dependent VEGF-C signaling. JCI INSIGHT, 5(14). doi:10.1172/jci.insight.137652

Fish, J. E., Flores-Suarez, C. P., Boudreau, E., Herman, A. M., Gutierrez, M. C., Gustafson, D., . . . Wythe, J. D. (2020). Somatic Gain of KRAS Function in the Endothelium Is Sufficient to Cause Vascular Malformations That Require MEK but Not PI3K Signaling. CIRCULATION RESEARCH, 127(6), 727-743. doi:10.1161/CIRCRESAHA.119.316500

Ellis, L. V., Cain, M. P., Hutchison, V., Flodby, P., Crandall, E. D., Borok, Z., . . . Chen, J. (2020). Epithelial Vegfa Specifies a Distinct Endothelial Population in the Mouse Lung. DEVELOPMENTAL CELL, 52(5), 617-+. doi:10.1016/j.devcel.2020.01.009

2019

Hong, S. -H., Herman, A. M., Stephenson, J. M., Wu, T., Bahadur, A. N., Burns, A. R., . . . Wythe, J. D. (2020). Development of barium-based low viscosity contrast agents for micro CT vascular casting: Application to 3D visualization of the adult mouse cerebrovasculature. JOURNAL OF NEUROSCIENCE RESEARCH, 98(2), 312-324. doi:10.1002/jnr.24539

Hill, M. C., Kadow, Z. A., Li, L., Tran, T. T., Wythe, J. D., & Martin, J. F. (2019). A cellular atlas of Pitx2-dependent cardiac development. DEVELOPMENT, 146(12). doi:10.1242/dev.180398

Gutierrez, A. C., Gutierrez, M. C., Rhyner, A. M., Ruiz, O. E., Eisenhoffer, G. T., & Wythe, J. D. (2019). FishNET: An automated relational database for zebrafish colony management. PLOS BIOLOGY, 17(6). doi:10.1371/journal.pbio.3000343

2018

Wang, K., Zhao, S., Liu, B., Zhang, Q., Li, Y., Liu, J., . . . Wu, N. (2018). Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM). JOURNAL OF MEDICAL GENETICS, 55(10), 675-684. doi:10.1136/jmedgenet-2017-105224

Xiao, Y., Hill, M. C., Zhang, M., Martin, T. J., Morikawa, Y., Wang, S., . . . Martin, J. F. (2018). Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development. DEVELOPMENTAL CELL, 45(2), 153-+. doi:10.1016/j.devcel.2018.03.019

Herman, A. M., Rhyner, A. M., Devine, W. P., Marrelli, S. P., Bruneau, B. G., & Wythe, J. D. (2018). A novel reporter allele for monitoring Dll4 expression within the embryonic and adult mouse. BIOLOGY OPEN, 7(3). doi:10.1242/bio.026799

Nikolaev, S. I., Vetiska, S., Bonilla, X., Boudreau, E., Jauhiainen, S., Jahromi, B. R., . . . Radovanovic, I. (2018). Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain. NEW ENGLAND JOURNAL OF MEDICINE, 378(3), 250-261. doi:10.1056/NEJMoa1709449

2017

Fish, J. E., Gutierrez, M. C., Dang, L. T., Khyzha, N., Chen, Z., Veitch, S., . . . Wythe, J. D. (2017). Dynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network. DEVELOPMENT, 144(13), 2428-2444. doi:10.1242/dev.146050

2016

Liu, Q., Zhang, H., Tian, X., He, L., Huang, X., Tan, Z., . . . Zhou, B. (2016). Smooth muscle origin of postnatal 2nd CVP is pre-determined in early embryo. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 471(4), 430-436. doi:10.1016/j.bbrc.2016.02.062

He, L., Liu, Q., Hu, T., Huang, X., Zhang, H., Tian, X., . . . Zhou, B. (2016). Genetic lineage tracing discloses arteriogenesis as the main mechanism for collateral growth in the mouse heart. CARDIOVASCULAR RESEARCH, 109(3), 419-430. doi:10.1093/cvr/cvw005

2015

Wang, J., Xiao, Y., Hsu, C. -W., Martinez-Traverso, I. M., Zhang, M., Bai, Y., . . . Martin, J. F. (2016). Yap and Taz play a crucial role in neural crest-derived craniofacial development. DEVELOPMENT, 143(3), 504-515. doi:10.1242/dev.126920

Lizama, C. O., Hawkins, J. S., Schmitt, C. E., Bos, F. L., Zape, J. P., Cautivo, K. M., . . . Zovein, A. C. (2015). Repression of arterial genes in hemogenic endothelium is sufficient for haematopoietic fate acquisition. NATURE COMMUNICATIONS, 6. doi:10.1038/ncomms8739

Fish, J. E., & Wythe, J. D. (2015). The Molecular Regulation of Arteriovenous Specification and Maintenance. DEVELOPMENTAL DYNAMICS, 244(3), 391-409. doi:10.1002/dvdy.24252

Liu, Q., Hu, T., He, L., Huang, X., Tian, X., Zhang, H., . . . Zhou, B. (2015). Genetic targeting of sprouting angiogenesis using Apln-CreER. Nature Communications, 6. doi:10.1038/ncomms7020

2014

Devine, W. P., Wythe, J. D., George, M., Koshiba-Takeuchi, K., & Bruneau, B. G. (2014). Early Patterning and Specification of Cardiac Progenitors in Gastrulating Mesoderm. ELIFE, 3. doi:10.7554/eLife.03848

He, L., Tian, X., Zhang, H., Wythe, J. D., & Zhou, B. (2014). Fabp4-CreER lineage tracing reveals two distinctive coronary vascular populations. JOURNAL OF CELLULAR AND MOLECULAR MEDICINE, 18(11), 2152-2156. doi:10.1111/jcmm.12415

2013

Wythe, J. D., Dang, L. T. H., Devine, W. P., Boudreau, E., Artap, S. T., He, D., . . . Fish, J. E. (2013). ETS Factors Regulate Vegf-Dependent Arterial Specification. DEVELOPMENTAL CELL, 26(1), 45-58. doi:10.1016/j.devcel.2013.06.007

2011

Qian, L., Wythe, J. D., Liu, J., Cartry, J., Vogler, G., Mohapatra, B., . . . Bodmer, R. (2011). Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species. JOURNAL OF CELL BIOLOGY, 193(7), 1181-1196. doi:10.1083/jcb.201006114

Wythe, J. D., Jurynec, M. J., Urness, L. D., Jones, C. A., Sabeh, M. K., Werdich, A. A., . . . Li, D. Y. (2011). Hadp1, a newly identified pleckstrin homology domain protein, is required for cardiac contractility in zebrafish. DISEASE MODELS & MECHANISMS, 4(5), 607-621. doi:10.1242/dmm.002204

Fish, J. E., Wythe, J. D., Xiao, T., Bruneau, B. G., Stainier, D. Y. R., Srivastava, D., & Woo, S. (2011). A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish. DEVELOPMENT, 138(7), 1409-1419. doi:10.1242/dev.060046