https://www.wythelab.com/

 

 

Research Disciplines

Cerebrovascular development, Cancer Neuroscience, Vascular Pathologies/Vascular Dementia

 

Research Interests

Cardiovascular Development and Cerebrovascular Pathologies

 

Research Description

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.

 

Selected Publications

2022

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, 121729. doi:10.1016/j.biomaterials.2022.121729

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), 28-44. doi:10.1038/s44161-021-00002-8

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

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

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

Carlson, J. C., Cantu Gutierrez, M., 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

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

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

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

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

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

2019

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

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

2018

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

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

Wang, K., Zhao, S., Liu, B., Zhang, Q., Li, Y., Liu, J., . . . Wu, N. (2018). Perturbations of BMP/TGF-beta 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

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

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

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

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

2015

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

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

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

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

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