# A novel chemical genetic approach reveals paralog-specific role of ERK1/2 in mouse embryonic stem cell fate control

## TL;DR

A new approach shows that ERK1 and ERK2 have unique roles in controlling mouse stem cell renewal and differentiation.

## Contribution

A chemical genetic method reveals paralog-specific functions of ERK1/2 in mouse embryonic stem cell fate.

## Key findings

- ERK1/2 are not essential for mouse ESC survival and self-renewal.
- Inhibiting both ERK1 and ERK2 with GSK3 inhibition maintains ESC self-renewal.
- ERK1 inhibition promotes mesendoderm differentiation, unlike ERK2 inhibition.

## Abstract

Introduction: Mouse embryonic stem cell (ESC) self-renewal can be maintained through dual inhibition of GSK3 and MEK kinases. MEK has two highly homologous downstream kinases, extracellular signal-regulated kinase 1 and 2 (ERK1/2). However, the exact roles of ERK1/2 in mouse ESC self-renewal and differentiation remain unclear.

Methods: We selectively deleted or inhibited ERK1, ERK2, or both using genetic and chemical genetic approaches combined with small molecule inhibitors. The effects of ERK paralog-specific inhibition on mouse ESC self-renewal and differentiation were then assessed.

Results: ERK1/2 were found to be dispensable for mouse ESC survival and self-renewal. The inhibition of both ERK paralogs, in conjunction with GSK3 inhibition, was sufficient to maintain mouse ESC self-renewal. In contrast, selective deletion or inhibition of only one ERK paralog did not mimic the effect of MEK inhibition in promoting mouse ESC self-renewal. Regarding ESC differentiation, inhibition of ERK1/2 prevented mesendoderm differentiation. Additionally, selective inhibition of ERK1, but not ERK2, promoted mesendoderm differentiation.

Discussion: These findings suggest that ERK1 and ERK2 have both overlapping and distinct roles in regulating ESC self-renewal and differentiation. This study provides new insights into the molecular mechanisms of ERK1/2 in governing ESC maintenance and lineage commitment, potentially informing future strategies for controlling stem cell fate in research and therapeutic applications.