Abstract
The Notch pathway controls proliferation during development and in adulthood, and is frequently affected in many disorders. However, the genetic sensitivity and multi-layered transcriptional properties of the Notch pathway has made its molecular decoding challenging. Here, we address the complexity of Notch signaling with respect to proliferation, using the developing Drosophila CNS as model. We find that a Notch/Su(H)/E(spl)-HLH cascade specifically controls daughter, but not progenitor proliferation. Additionally, we find that different E(spl)-HLH genes are required in different neuroblast lineages. The Notch/Su(H)/E(spl)-HLH cascade alters daughter proliferation by regulating four key cell cycle factors: Cyclin E, String/Cdc25, E2f and Dacapo (mammalian p21CIP1/p27KIP1/p57Kip2). ChIP and DamID analysis of Su(H) and E(spl)-HLH indicates direct transcriptional regulation of the cell cycle genes, and of the Notch pathway itself. These results point to a multi-level signaling model and may help shed light on the dichotomous proliferative role of Notch signaling in many other systems.
Highlights
The Notch signal transduction pathway plays a central role during animal development, and is critical for tissue homeostasis during adulthood [1]
The precise flow of events from receptor cleavage to diverse target gene regulation is often unclear: which specific E(spl)HLH genes are activated, which other target genes are regulated, and at what level(s)? For instance, while Notch signaling is known to regulate cell cycle genes [12], it is unclear whether this regulation is direct via Notch-Intracellular Domain truncation (NICD)-Mam-Su(H), or indirect via the E(spl)-HLH factors; because the genome-wide binding profiles of E(spl)-HLH factors have not been addressed
The embryonic Drosophila CNS can be subdivided into the brain and the ventral nerve cord (VNC); here we focus on the VNC
Summary
The Notch signal transduction pathway plays a central role during animal development, and is critical for tissue homeostasis during adulthood [1]. A delayed response to Notch activation likely involves the repression of secondary target genes by the E(spl)-HLH factors During early neurogenesis, these E(spl)-HLH factors act by antagonizing the activity and expression of the proneural bHLH factors [10]. While Notch signaling is known to regulate cell cycle genes [12], it is unclear whether this regulation is direct via NICD-Mam-Su(H), or indirect via the E(spl)-HLH factors; because the genome-wide binding profiles of E(spl)-HLH factors have not been addressed. Whether differences in E(spl)-HLH expression and function contribute to the cell-specific response to Notch receptor activation remains completely unknown, primarily because extensive genetic redundancy has precluded the identification of single-gene mutations and functions for any one of these genes [13,14,15,16]
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