Axonal localization of the fragile X family of RNA binding proteins is conserved across mammals

Abstract

Spatial segregation of proteins to neuronal axons arises in part from local translation of mRNAs that are first transported into axons in ribonucleoprotein particles (RNPs), complexes containing mRNAs and RNA binding proteins. Understanding the importance of local translation for a particular circuit requires not only identifying axonal RNPs and their mRNA cargoes, but also whether these RNPs are broadly conserved or restricted to only a few species. Fragile X granules (FXGs) are axonal RNPs containing the fragile X related family of RNA binding proteins along with ribosomes and specific mRNAs. FXGs were previously identified in mouse, rat, and human brains in a conserved subset of neuronal circuits but with species-dependent developmental profiles. Here, we asked whether FXGs are a broadly conserved feature of the mammalian brain and sought to better understand the species-dependent developmental expression pattern. We found FXGs in a conserved subset of neurons and circuits in the brains of every examined species that together include mammalian taxa separated by up to 160 million years of divergent evolution. A developmental analysis of rodents revealed that FXG expression in frontal cortex and olfactory bulb followed consistent patterns in all species examined. In contrast, FXGs in hippocampal mossy fibers increased in abundance across development for most species but decreased across development in guinea pigs and members of the Mus genus, animals that navigate particularly small home ranges in the wild. The widespread conservation of FXGs suggests that axonal translation is an ancient, conserved mechanism for regulating the proteome of mammalian axons. K E Y W O R D S axonal translation, local protein synthesis, RNA binding proteins, RRID AB_10805421, RRID AB_2278530, RRID AB_2737297, RRID AB_528262

Fmr1 exon 14 skipping in late embryonic development of the rat forebrain

“…In the postnatal CNS, FMRP has been mostly described as a translational repressor of dendritic mRNAs in glutamatergic synapses, regulating synaptic plasticity, in particular long-term depression [ 8 ]. However, FMRP is observed in additional neuronal types [ 15 , 16 ], distinct subcellular distribution such as in the axonal compartment [ 11 , 13 , 17 ], and other cell types as glia [ 18 ]. During cerebral corticogenesis of the mouse embryo, loss of Fmrp depletes radial glia cells by increasing their differentiation into intermediate progenitor cells [ 19 ], and affects the multipolar to bipolar neuronal transition in the cortical plate [ 20 ].…”