Endogenous FGFs drive ERK-dependent cell fate patterning in 2D human gastruloids

Area of Science:

• Developmental Biology
• Cell Signaling
• Human Embryogenesis

Background:

• Fibroblast Growth Factor (FGF) signaling is crucial but poorly understood in mammalian gastrulation.
• Investigating FGF roles in human gastrulation is essential for understanding early development.

Purpose of the Study:

• To elucidate the function of FGF signaling in human gastrulation using a 2D gastruloid model.
• To identify specific FGF ligands and their roles in primitive streak (PS)-like cell formation and differentiation.

Main Methods:

• Utilized a 2D gastruloid model to simulate human gastrulation.
• Analyzed FGF-dependent ERK activity patterns.
• Performed single-cell transcriptome analysis to identify FGF ligand expression.
• Investigated the effects of FGF knockdown and receptor inhibition on PS-like differentiation.

Main Results:

• Observed FGF-dependent ERK activity preceding and during PS-like cell emergence.
• FGF4 and FGF17 are specifically expressed in PS-like cells and are required for differentiation.
• FGF8 expression is displaced and its knockdown expands PS-like cells, suggesting an inhibitory role.
• FGF signaling acts through basolateral FGF receptor 1 (FGFR1) to induce PS-like cells.

Conclusions:

• FGF4 and FGF17 signaling via FGFR1 are critical for inducing human PS-like cells and derivatives in gastruloids.
• FGF-dependent ERK signaling plays a novel, essential role in early human development.
• FGF8 may act as a negative regulator of PS-like differentiation, contrasting with its role in mouse embryos.