Mutant FGFR3 restricts bone yet expands cortex via ERK-mediated self-repression

Abstract

FGFR3 gain-of-function mutations cause achondroplasia 1,2, the most common form of dwarfism, yet trigger paradoxical cerebral overgrowth and skeletal stunting 3-9. Here, we demonstrate that Fgfr3-K644E mutant drives enhanced ERK activation, which then represses Fgfr3 expression and downregulates ERK signaling. In the developing cortex, this mechanism transiently expands cortical stem cells by activating ERK, then shifts signaling to downregulate Fgfr3/ERK/PKA and enhance YAP/TAZ, promoting cerebral overgrowth and premature ependymal maturation. In growing bones, Fgfr3-K644E mutant first elevates ERK to inhibit chondrocyte pre-hypertrophy, then downregulates Fgfr3/ERK/PKA and upregulates YAP/TAZ to accelerate premature hypertrophy and ossification. Our findings establish that FGFR3 mutations limit bone yet expand cortical size via an ERK negative feedback loop, revealing a unified disease mechanism and novel therapeutic targets.