Intracellular pH dynamics regulates intestinal stem cell fate

Emerging evidence is revealing critical roles of intracellular pH (pHi) in development, but it remains unclear whether pHi regulates stem cell fate specification. We find that pHi dynamics is a key regulator of cell fate in the mouse intestinal stem cell lineage. We identify a pHi gradient along the intestinal crypt axis and find that dissipating this gradient inhibits crypt budding due to loss Paneth cell differentiation. Mechanistically, decreasing pHi biases intestinal stem cell fate toward the absorptive and away from the secretory lineage, by regulating the activity of the lineage transcription factor Atoh1. Our findings reveal a previously unrecognized role for pHi dynamics in the specification of cell fate within an adult stem cell lineage.