Fluorescein-based SynNotch adaptors for regulating gene expression responses to diverse extracellular and matrix-based cues

Jeremy C. Tran, Christopher J. Kuffner, Alexander M. Marzilli, Ryan Emily Miller, Zachary E. Silfen, Jeffrey B. McMahan, D. Christopher Sloas, Christopher S. Chen and John T. Ngo ()
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Jeremy C. Tran: Boston University
Christopher J. Kuffner: Boston University
Alexander M. Marzilli: Boston University
Ryan Emily Miller: Boston University
Zachary E. Silfen: Boston University
Jeffrey B. McMahan: Boston University
D. Christopher Sloas: Boston University
Christopher S. Chen: Boston University
John T. Ngo: Boston University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Synthetic Notch (SynNotch) receptors function like natural Notch proteins and can be used to install customized sense-and-respond capabilities into mammalian cells. Here, we introduce an adaptor-based strategy for regulating SynNotch activity via fluorescein isomers and analogs. Using an optimized fluorescein-binding SynNotch receptor, we describe ways to chemically control SynNotch signaling, including an approach based on a bio-orthogonal chemical ligation and a spatially controllable strategy via the photo-patterned uncaging of an o-nitrobenzyl-caged fluorescein conjugate. We further show that fluorescein-conjugated extracellular matrix (ECM)-binding peptides can be used to regulate SynNotch activity depending on the folding state of collagen-based ECM networks. To demonstrate the utility of these tools, we apply them to activate dose-dependent gene expression responses and to induce myogenic-like phenotypes in multipotent fibroblasts with spatiotemporal and microenvironmental control. Overall, we introduce an optimized fluorescein-binding SynNotch as a versatile tool for regulating transcriptional responses to ligands based on the clinically-approved fluorescein dye.

Date: 2025
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DOI: 10.1038/s41467-025-56148-7

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