Imp Promotes Axonal Remodeling by Regulating profilin mRNA during Brain Development

Abstract

Neuronal remodeling is essential for the refinement of neuronal circuits in response to developmental cues [1-4]. Although this process involves pruning or retraction of axonal projections followed by axonal regrowth and branching, how these steps are controlled is poorly understood. Drosophila mushroom body (MB) γ neurons provide a paradigm for the study of neuronal remodeling, as their larval axonal branches are pruned during metamorphosis and re-extend to form adult-specific branches [5]. Here, we identify the RNA binding protein Imp as a key regulator of axonal remodeling. Imp is the sole fly member of a conserved family of proteins that bind target mRNAs to promote their subcellular targeting [6-12]. We show that whereas Imp is dispensable for the initial growth of MB γ neuron axons, it is required for the regrowth and ramification of axonal branches that have undergone pruning. Furthermore, Imp is actively transported to axons undergoing developmental remodeling. Finally, we demonstrate that profilin mRNA is a direct and functional target of Imp that localizes to axons and controls axonal regrowth. Our study reveals that mRNA localization machineries are actively recruited to axons upon remodeling and suggests a role of mRNA transport in developmentally programmed rewiring of neuronal circuits during brain maturation.

Regulatory Mechanisms of Metamorphic Neuronal Remodeling Revealed Through a Genome-Wide Modifier Screen in Drosophila melanogaster

“…However, it is also possible that different or overlapping mechanisms may control the growth of cell bodies and neurites. While some signaling pathways and factors are known to regulate neurite morphology (Williams and Truman 2005b; Kurtz et al 2011; Yaniv et al 2012; Gu et al 2014; Medioni et al 2014), the factors that shape neuron somata during neuronal remodeling remain undefined. If these mechanisms are different, then this system will provide an opportunity to understand distinct regulatory mechanisms controlling soma and neurite growth.…”

Imp/IGF2BP levels modulate individual neural stem cell growth and division through myc mRNA stability

“…We identified 318 mRNA targets that were significantly enriched in the Imp pulldown compared to input brain RNAseq (using the thresholds DESeq2.padj < 0.01 and DESeq2.log2FoldChange > 2) ( Figure S2A, B, Supplemental Table 1). The list of targets includes known Imp targets such as chickadee (target rank: 37) (Medioni et al, 2014), as well as mRNAs that have previously been shown to be regulated by Imp. Imp binds syp mRNA (target rank: 103), which indicates a post-transcriptional mechanism for the previously observed negative regulation of Syp by Imp (Liu et al, 2015).…”

Spatially and temporally regulating translation via mRNA‐binding proteins in cellular and neuronal function

“…Growth factors such as BDNF and netrin can induce translation to occur in a spatially restricted fashion to facilitate growth cone turning and branching toward guidance cues. One of the best‐studied mRNA‐binding proteins in this process, and also highly conserved proteins, has been the mRNA‐binding protein ZBP1/IMP1/IGF2BP1/VICKZ/Vg1RBP . Mechanistically acting as a translational repressor and localizing factor for mRNA, the ZBP1 family of proteins keeps messenger RNA quiescence until it reaches its destination, where stimulus‐induced src kinase phosphorylation of the protein relieves translational repression and allows local protein synthesis.…”