FGFR-mediated ERK1/2 signaling contributes to mesendoderm and definitive endoderm formation in vitro

Hwee Hui Lau; Nur Shabrina Amirruddin; Larry Sai Weng Loo; Jun Wei Chan; Elhadi Iich; Vidhya Gomathi Krishnan; Shawn Hoon; Adrian Kee Keong Teo

doi:10.1016/j.isci.2023.107265

FGFR-mediated ERK1/2 signaling contributes to mesendoderm and definitive endoderm formation in vitro

iScience. 2023 Jul 3;26(8):107265. doi: 10.1016/j.isci.2023.107265. eCollection 2023 Aug 18.

Authors

Hwee Hui Lau^{1

2}, Nur Shabrina Amirruddin^{1

3}, Larry Sai Weng Loo^{1

2}, Jun Wei Chan¹, Elhadi Iich¹, Vidhya Gomathi Krishnan⁴, Shawn Hoon⁴, Adrian Kee Keong Teo^{1

3

5

6}

Affiliations

¹ Stem Cells and Diabetes Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A∗STAR), Proteos, Singapore, Singapore.
² School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.
³ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴ Molecular Engineering Lab, IMCB, Proteos, Singapore, Singapore.
⁵ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁶ Precision Medicine Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Abstract

The differentiation of human pluripotent stem cells into the SOX17⁺ definitive endoderm (DE) germ layer is important for generating tissues for regenerative medicine. Multiple developmental and stem cell studies have demonstrated that Activin/Nodal signaling is the primary driver of definitive endoderm formation. Here, we uncover that the FGF2-FGFR-ERK1/2 signaling contributes to mesendoderm and SOX17⁺ DE formation. Without ERK1/2 signaling, the Activin/Nodal signaling is insufficient to drive mesendoderm and DE formation. Besides FGF2-FGFR-mediated signaling, IGF1R signaling possibly contributes to the ERK1/2 signaling for DE formation. We identified a temporal relationship between Activin/Nodal-SMAD2 and FGF2-FGFR-ERK1/2 signaling in which Activin/Nodal-SMAD2 participates in the initiation of mesendoderm and DE specification that is followed by increasing activity of FGF2-FGFR-ERK1/2 to facilitate and permit the successful generation of SOX17⁺ DE. Overall, besides the role of Activin/Nodal signaling for DE formation, our findings shed light on the contribution of ERK1/2 signaling for mesendoderm and DE formation.

Keywords: Biological sciences; Developmental biology; Embryology; Molecular biology.