Stanford Advisors

All Publications

  • GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism. Development (Cambridge, England) Yuki, K., Vallon, M., Ding, J., Rada, C. C., Tang, A. T., Vilches-Moure, J. G., McCormick, A. K., Echeverri, M. F., Alwahabi, S., Braunger, B. M., Ergün, S., Kahn, M. L., Kuo, C. J. 2024


    The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion 7-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7, which is transferred to Frizzled (FZD) to initiate canonical b-catenin signaling. GPR124 remains enigmatic; while its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124/FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function by mouse deletion (Gpr124ΔC). Despite inefficiently expressed GPR124ΔC protein, Gpr124ΔC/ΔC mice could be born with normal cerebral cortex angiogenesis, versus Gpr124-/- embryonic lethality, forebrain avascularity and hemorrhage. Gpr124ΔC/ΔC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124ΔC protein expression. Further, Gpr124ΔC and recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124-regulated CNS forebrain angiogenesis and BBB function is exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion 7-pass transmembrane receptors.

    View details for DOI 10.1242/dev.202794

    View details for PubMedID 38682276

  • Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice. Nature communications Ding, J., Lee, S., Vlahos, L., Yuki, K., Rada, C. C., van Unen, V., Vuppalapaty, M., Chen, H., Sura, A., McCormick, A. K., Tomaske, M., Alwahabi, S., Nguyen, H., Nowatzke, W., Kim, L., Kelly, L., Vollrath, D., Califano, A., Yeh, W., Li, Y., Kuo, C. J. 2023; 14 (1): 2947


    Derangements of the blood-brain barrier (BBB) or blood-retinal barrier (BRB) occur in disorders ranging from stroke, cancer, diabetic retinopathy, and Alzheimer's disease. The Norrin/FZD4/TSPAN12 pathway activates WNT/beta-catenin signaling, which is essential for BBB and BRB function. However, systemic pharmacologic FZD4 stimulation is hindered by obligate palmitoylation and insolubility of native WNTs and suboptimal properties of the FZD4-selective ligand Norrin. Here, we develop L6-F4-2, a non-lipidated, FZD4-specific surrogate which significantly improves subpicomolar affinity versus native Norrin. In Norrin knockout (NdpKO) mice, L6-F4-2 not only potently reverses neonatal retinal angiogenesis deficits, but also restores BRB and BBB function. In adult C57Bl/6J mice, post-stroke systemic delivery of L6-F4-2 strongly reduces BBB permeability, infarction, and edema, while improving neurologic score and capillary pericyte coverage. Our findings reveal systemic efficacy of a bioengineered FZD4-selective WNT surrogate during ischemic BBB dysfunction, with potential applicability to adult CNS disorders characterized by an aberrant blood-brain barrier.

    View details for DOI 10.1038/s41467-023-37689-1

    View details for PubMedID 37268690

  • Regulation of the Blood-Brain Barrier in Health and Disease. Cold Spring Harbor perspectives in medicine Rada, C. C., Yuki, K., Ding, J., Kuo, C. J. 2023


    The neurovascular unit is a dynamic microenvironment with tightly controlled signaling and transport coordinated by the blood-brain barrier (BBB). A properly functioning BBB allows sufficient movement of ions and macromolecules to meet the high metabolic demand of the central nervous system (CNS), while protecting the brain from pathogenic and noxious insults. This review describes the main cell types comprising the BBB and unique molecular signatures of these cells. Additionally, major signaling pathways for BBB development and maintenance are highlighted. Finally, we describe the pathophysiology of BBB diseases, their relationship to barrier dysfunction, and identify avenues for therapeutic intervention.

    View details for DOI 10.1101/cshperspect.a041191

    View details for PubMedID 36987582