Notch controls early temporal factor expression to control timing of Mushroom body neuroblast apoptosis

Abstract

The neurogenic period, where neural stem cells (NSCs) proliferate to produce molecularly distinct progeny in the developing brain, is a critical time of growth in many organisms. Proper brain development is crucial for survival and requires strict regulation of NSC divisions along a set developmental timeline. InDrosophilaNSCs known as neuroblasts (NBs), cell intrinsic programs integrate with extrinsic cues to control periods of rapid growth through temporal patterning genes. Without regulation, NSCs can under proliferate leading to diseases like microcephaly and autism spectrum disorders, or over proliferate leading to macrocephaly and tumors. We know programs to control timing of proliferation and elimination of NSCs exist, but many elements of temporal cassettes are still unclear. What genes may be upstream to regulate known temporal programs to control when certain progeny are produced have not been fully identified, leaving a gap in our understanding. To address these questions, we carried out a large-scale RNAi screen aimed at identifying genes required for NSC elimination. We identified Notch and its ligand, Delta. When Notch pathway activity is reduced in NSCs, we found premature elimination of an important subset of neuroblasts called the mushroom body neuroblasts (MBNBs). These MBNBs produce the neurons responsible for formation of the evolutionarily conserved structure called the mushroom body (MB), which is involved in olfactory based learning and memory. MBNBs with reduced Notch pathway activity also experienced defects in MB structure. Furthermore, we determined that temporal patterning is disrupted primarily through loss of early temporal factor expression. In this work, we find that cell signaling pathways that involve the receptor Notch and its ligand. Delta function to regulate NB proliferation inDrosophila melanogasterby regulating early temporal factor expression.

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

“…Our dataset captures Imp and Syp targets involved in diverse biological and molecular functions, including key regulators of NSC growth and quiescence, energy metabolism, intracellular signalling, hormone response, and tumourigenic potential. This indicates the versatility of Imp and Syp gradients in mediating intrinsic NB lineage functions as well as responding to extrinsic signals (Branham et al, 2024; Islam and Erclik, 2022; Rossi and Desplan, 2020; Syed et al, 2017). Notably, both Imp and Syp bind to many transcripts encoding cytoskeleton and axonogenesis regulators (Figure 2A).…”

“…Furthermore, the protracted nature of Imp and Syp gradients allows integration of extrinsic signals into the intrinsic patterning programme (e.g. steroid hormone, Activin and Notch signalling) (Branham et al, 2024; Rossi and Desplan, 2020; Syed et al, 2017). Although some individual downstream targets of Imp and Syp have been characterised in the studies cited above, the complete RNA interactomes and their temporal variations remain unexplored.…”