hnRNP Q regulates IRES-mediated fmr1 translation in neurons

Abstract

Fragile X syndrome (FXS) caused by loss of fragile X mental retardation protein (FMRP) is the most common cause of inherited intellectual disability. Numerous studies show that FMRP is a RNA binding protein that regulates translation of its binding targets and plays key roles in neuronal functions. However, the regulatory mechanism for FMRP expression is incompletely understood. Conflicting results regarding internal ribosome entry site (IRES)-mediated fmr1 translation were reported. Here, we unambiguously demonstrated that the fmr1 gene, which encodes FMRP, exploits both IRES-mediated translation and canonical cap-dependent translation. Furthermore, we found that heterogeneous nuclear ribonucleoprotein Q (hnRNP-Q) acts as IRES transacting factor (ITAF) for IRES-mediated fmr1 translation in neurons. We also showed that semaphorin 3A (Sema3A) induced axonal growth cone collapse is due to upregulation of hnRNP-Q and subsequent IRES-mediated expression of FMRP. These data elucidate the regulatory mechanism of FMRP expression and its role in axonal growth cone collapse.