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

FGFR3 gain-of-function mutations cause achondroplasia, the most common form of dwarfism, yet trigger paradoxical cerebral overgrowth and skeletal stunting. Here， we demonstrate that mutant FGFR3 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 premature ependymal maturation and cerebral overgrowth. In growing bones, mutant Fgfr3 first elevates ERK to inhibit chondrocyte hypertrophy, then downregulates Fgfr3/ERK/PKA and upregulates YAP/TAZ to accelerate hypertrophy and ossification. Our findings establish that FGFR3 mutations limit bone yet expand brain size via an ERK negative feedback loop, revealing a unified disease mechanism and novel therapeutic targets.