Glial Hedgehog signalling and lipid metabolism regulate neural stem cell proliferation in Drosophila

Abstract

The final size and function of the adult central nervous system (CNS) are determined by neuronal lineages generated by neural stem cells (NSCs) in the developing brain. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-autonomous glial regulation of NB proliferation. We show that lipid droplets (LDs) which reside within the glial niche are closely associated with the signalling molecule Hedgehog (Hh). Under physiological conditions, cortex glial Hh is autonomously required to sustain niche chamber formation. Upon FGF-mediated cortex glial overgrowth, glial Hh non-autonomously activates Hh signalling in the NBs, which in turn disrupts NB cell cycle progression and its ability to produce neurons. Glial Hh's ability to signal to NB is further modulated by lipid storage regulator lipid storage droplet-2 (Lsd-2) and de novo lipogenesis gene fatty acid synthase 1 (Fasn1). Together, our data suggest that glial-derived Hh modified by lipid metabolism mechanisms can affect the neighbouring NB's ability to proliferate and produce neurons.

Functions of Stress-Induced Lipid Droplets in the Nervous System

“…In the invertebrate genetic model organism Drosophila, stress-induced LDs have been well characterized in both the developing and adult nervous systems ( Bailey et al, 2015 ; Liu et al, 2015 ). In the developing CNS, LDs form predominantly in cortex and subperineurial glia, which constitute the niche for multipotent self-renewing neural stem cells called neuroblasts, and they increase following exposure to hypoxia or oxidant chemicals ( Bailey et al, 2015 ; Kis et al, 2015 ; Dong et al, 2021 ). At adult stages, LDs are also present in glia of the CNS and increase during hypoxia ( Smolič et al, 2021 ).…”

“…Distinct from a role in mitochondrial regulation, glial LDs can also regulate the activity of the intercellular signalling protein Hedgehog (Hh). In cortex glia of the developing Drosophila CNS, a proportion of the total Hh protein colocalizes with markers of the LD surface ( Dong et al, 2021 ). Glial knockdown of a Drosophila Perilipin called Lipid storage droplet-2 (Lsd2), a negative regulator of ATGL, prevented glial overexpressed Hh from mediating an anti‐proliferative effect on neighbouring neural stem cells ( Dong et al, 2021 ).…”

“…In cortex glia of the developing Drosophila CNS, a proportion of the total Hh protein colocalizes with markers of the LD surface ( Dong et al, 2021 ). Glial knockdown of a Drosophila Perilipin called Lipid storage droplet-2 (Lsd2), a negative regulator of ATGL, prevented glial overexpressed Hh from mediating an anti‐proliferative effect on neighbouring neural stem cells ( Dong et al, 2021 ). It is therefore possible that the association of Hh with LDs modulates its secretion and/or activity.…”

An interplay between cellular growth and atypical fusion defines morphogenesis of a modular glial niche

“…CG perform genuine niche functions. They protect NSCs against oxidative stress and nutritional restriction 28,29 , support NSC cycling 30,31 and are essential for neuronal positioning and survival 25,27,30,32,33 .…”

“…CG perform genuine niche functions. They protect NSCs against oxidative stress and nutritional restriction 28,29 , support NSC cycling 30,31 and are essential for neuronal positioning and survival 25,27,30,32,33 . Importantly, CG network and NSC encasing are not present at the beginning of larval life, when NSCs are quiescent.…”