hnRNP Q regulates cap-independent 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 and regulates translation of its binding targets, which plays key roles in neuronal func- tions. However, the regulatory mechanism for FMRP expression is incom pletely understood. Conflicting results regarding internal ribosome entry site (IRES)-mediated fmr1 translation were reported. Here, we unambiguously demonstrate that the fmr1 gene encoding FMRP exploits both IRES-medi ated translation(cap-independent translation) and canonical cap-dependent translation. Furthermore, we find that heterogeneous nuclear ribonucleop- rotein Q (hnRNP-Q) acts as IRES transacting factor (ITAF) for IRES-mediated fmr1 translation in neurons. We also show 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.