Imp is required for timely exit from quiescence in Drosophila type II neuroblasts

Abstract

Stem cells must balance proliferation and quiescence, with excess proliferation favoring tumor formation, and premature quiescence preventing proper organogenesis. Drosophila brain neuroblasts are a model for investigating neural stem cell entry and exit from quiescence. Neuroblasts begin proliferating during embryogenesis, enter quiescence prior to larval hatching, and resume proliferation 12-30h after larval hatching. Here we focus on the mechanism used to exit quiescence, focusing on "type II" neuroblasts. There are 16 type II neuroblasts in the brain, and they undergo the same cycle of embryonic proliferation, quiescence, and proliferation as do most other brain neuroblasts. We focus on type II neuroblasts due to their similar lineage as outer radial glia in primates (both have extended lineages with intermediate neural progenitors), and because of the availability of specific markers for type II neuroblasts and their progeny. Here we characterize the role of Insulin-like growth factor II mRNA-binding protein (Imp) in type II neuroblast proliferation and quiescence. Imp has previously been shown to promote proliferation in type II neuroblasts, in part by acting antagonistically to another RNA-binding protein called Syncrip (Syp). Here we show that reducing Imp levels delays exit from quiescence in type II neuroblasts, acting independently of Syp, with Syp levels remaining low in both quiescent and newly proliferating type II neuroblasts. We conclude that Imp promotes exit from quiescence, a function closely related to its known role in promoting neuroblast proliferation.

Imp and Sypin vivotemporal RNA interactomes uncover networks of temporal regulators ofDrosophilabrain development

“…Although Imp and Syp targets were generally enriched for similar biological processes (Figure 2B), Imp targets were more strongly enriched for ‘cell growth’ and ‘response to insulin’ terms (Figure 2E). Cellular growth and insulin signalling are pivotal processes involved in reactivation of quiescent cells (Chell and Brand, 2010; Homem and Knoblich, 2012), and Imp has been shown to influence the timing of NB reactivation in early larval stages (Munroe et al, 2022). Indeed, the majority of the NB quiescence regulators are identified as Imp targets (Figure 2F), suggesting Imp may act on NB reactivation through these transcripts.…”

“…Similarly, we tested the role of Imp in regulating an early-born neuron marker Ldh in the L1 brain (24h ALH). We used a temporal imp knockdown system using insc- GAL4 and tub- GAL80ts (Figure S4G) because constitutive knockdown of imp results in NB reactivation defects (Munroe et al, 2022). In this system, loss of imp resulted in the destabilisation of Ldh in the NB lineage (Figure 4E and S4H).…”

“…Imp and Syp levels are known to influence specification of the mushroom body (Liu et al, 2020, 2015), motor neurons (Guan et al, 2022), the central complex (Hamid et al, 2023), and the visual system (Arain et al, 2022). Beyond fate patterning, they also regulate NB quiescence exit (Munroe et al, 2022), NB growth and self-renewal (Hailstone et al, 2020; Landskron et al, 2018; Samuels et al, 2020b), NB decommissioning (Pahl et al, 2019; C. P. Yang et al, 2017), synaptic transmission (Boylan et al, 2008; Halstead et al, 2014; Hansen et al, 2015; Medioni et al, 2014; Titlow et al, 2020), and fly behaviour (Hamid et al, 2023; Samuels et al, 2020a). Furthermore, the protracted nature of Imp and Syp gradients allows integration of extrinsic signals into the intrinsic patterning programme (e.g.…”

The RNA-binding protein, Imp specifies olfactory navigation circuitry and behavior inDrosophila

“…To test if Imp is sufficient for generating VT029515 neurons, we ectopically expressed Imp in Type II neural stem cells, Type II>UAS-Imp. In these animals, Imp is now expressed in young as well as late Type II neural stem cells 83 . We observed a ~3-fold increase in the number of VT029515 cell bodies with Imp overexpression.…”

Imp is expressed in INPs and newborn neurons where it regulates neuropil targeting in the central complex

“…T2NBs are formed in the embryonic brain [ 1 , 32 ], undergo several divisions, and then both T2NBs and INPs undergo a period of quiescence [ 7 , 14 , 19 ]. They exit quiescence 12-36 h after larval hatching (ALH; subsequently all larval ages are given as ALH) [ 19 ]. As T2NBs divide and age, they express different temporal factors in a process called temporal patterning.…”