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

Abstract

The numerous neurons and glia that form the brain originate from tightly controlled growth and division of neural stem cells, regulated systemically by known extrinsic signals. However, the intrinsic mechanisms that control the characteristic proliferation rates of individual neural stem cells are unknown. Here, we show that the size and division rates of Drosophila neural stem cells (neuroblasts) are controlled by the highly conserved RNA binding protein Imp (IGF2BP), via one of its top binding targets in the brain, myc mRNA. We show that Imp stabilises myc mRNA leading to increased Myc protein levels, larger neuroblasts, and faster division rates. Declining Imp levels throughout development limit myc mRNA stability to restrain neuroblast growth and division, while heterogeneous Imp expression correlates with myc mRNA stability between individual neuroblasts in the brain. We propose that Imp-dependent regulation of myc mRNA stability fine-tunes individual neural stem cell proliferation rates.

B Cell Division Capacity in Germinal Centers Depends on Myc Transcript Stabilization Through m6A mRNA Methylation and IGF2BP3 Functions

“…In non-mammalian model organisms and cell lines, IGF2BP paralogs enhance the stability of several mRNAs including Myc transcripts, and m 6 A has been shown to reinforce these mRNAprotein interactions (Huang et al, 2018;Palanichamy et al, 2016;Ren et al, 2020;Samuels et al, 2020). Our findings add a new role for this mRNA stabilization machinery in immune cells and demonstrate how IGF2BP3 controls cell fate in a mammalian organism.…”

“…IGF2BPs are a family of mRNA binding proteins that increase the mRNA lifetime of target genes and whose binding capacities are enhanced by m 6 A methylation (Huang et al, 2018;Palanichamy et al, 2016;Ren et al, 2020;Samuels et al, 2020). IGF2BP3 binds the 3'-UTR of Myc mRNA in cell lines and is the only paralog that is expressed in immune cells (Palanichamy et al, 2016).…”

MYC in Brain Development and Cancer

“…More recent studies implicate the regulation of Myc mRNA stability by the RNA-binding proteins Imp (conserved as mammalian Insulin Growth Factor (IGF) 2 mRNA-binding protein/IGF2BP2) and Imp antagonist Syp (Syncrip in mammals), as key determinants of neuroblast renewal [ 70 ]. Genome-wide single molecule fluorescent in situ hybridisation identified Myc as an Imp RNA binding target.…”

“…Moreover, Myc mRNA stability was increased following Imp overexpression. On the other hand, the Imp antagonist Syp reduced Myc mRNA stability indirectly by negatively regulating Imp [ 70 ]. Thus, knockdown of Imp in the neural lineage reduced the cell size and proliferation of type I neuroblasts, while Syp knockdown increased proliferative growth [ 70 ].…”

Neuronal upregulation of Prospero protein is driven by alternative mRNA polyadenylation and Syncrip-mediated mRNA stabilisation

“…Many key regulators in the brain also have complex gene structures such as multiple isoforms and long 3' UTRs, hallmarks of post-transcriptional mechanisms (Berger et al, 2012;Hilgers et al, 2011;Stoiber et al, 2015;Tekotte et al, 2002). Such genes include the temporal regulator neuronal fate, chinmo (Liu et al, 2015), driver of cell growth and division, myc (Samuels et al, 2019) and the mRNA-binding proteins, brat (Bello et al, 2006;Betschinger et al, 2006;Lee et al, 2006) and imp (Liu et al, 2015). Quantitative smFISH approaches combined with genetics and biochemistry will allow the detailed disentanglement of transcriptional and post-transcriptional mechanisms regulating these genes.…”