Notch signaling in Drosophila long-term memory formation

Abstract

Notch (N) is a cell surface receptor that mediates an evolutionarily ancient signaling pathway to control an extraordinarily broad spectrum of cell fates and developmental processes. To gain insights into the functions of N signaling in the adult brain, we examined the involvement of N in Drosophila olfactory learning and memory. Long-term memory (LTM) was disrupted by blocking N signaling in conditional mutants or by acutely induced expression of a dominant-negative N transgene. In contrast, neither learning nor early memory were affected. Furthermore, induced overexpression of a wild-type (normal) N transgene specifically enhanced LTM formation. These experiments demonstrate that N signaling contributes to LTM formation in the Drosophila adult brain.A ctivation of Notch (N) receptors has been linked to the specification of many cell types in both vertebrates and invertebrates (1). Binding of ligands such as Delta (2) causes cleavage of the intracellular domain of the N protein (3-5). The cleaved cytoplasmic domain of N (Nintra) enters the nucleus, in which it regulates expression of target genes (1). Intercellular communication mediated by N signaling consists of two different modes: lateral inhibitory signaling and inductive signaling. A prototypic example of lateral inhibitory signaling is that loss of N function causes a cluster of equivalent proneural cells to all assume the default neuronal fate rather than an epidermal fate (6). Inductive N signaling, on the other hand, mediates interactions between cells that are nonequivalent before the signal initiates, such as induction of cone cells by photoreceptor cells and specification of midline cells in the embryo (7-9).In contrast to the extensive understanding of the vital role of N in development, the significance of N signaling in adult brains has yet to be revealed, although there is continuous presence of N protein and its ligands in the adult vertebrate nervous system (10). It has been reported that N signaling regulates neurite outgrowth in mammals (11), and chronic reduction of N activity in adult fruit flies also leads to progressive neurological syndromes (12). Processing of N requires ␥-secretase activity, whereas presenilin (PS) is a critical component of the ␥-secretase complex (13). Mutations in the PS genes are associated with the early onset of Alzheimer's disease (14). Conditional knockout of the PS1 gene in mice is also associated with reduced clearance of hippocampal memory traces (15). Although involvement of N in these PS mutant phenotypes remains to be determined, it has been shown that N plays a role in PS-mediated formation of neural projections in postmitotic neurons necessary for learned thermotaxis in Caenorhabditis elegans (16). In the present study, we examined the role of N signaling in learning and memory in Drosophila.A Pavlovian procedure that pairs odors with foot-shock (17) was used in this study to assess the effects of N signaling on adult behavioral plasticity. Genetic analyses have demonstrated that memory formation afte...

Cytokine signaling through the JAK/STAT pathway is required for long-term memory in Drosophila

“…Identification of such target genes could be approached by using bioinformatics and/or transcription profiling. Recent profiling studies have identified a number of putative Stat92E target genes in the Drosophila eye disk and hematopoietic system (40,41), some of which include Notch signaling pathway genes that have already been implicated in LTM (42,43). Another mode of action of JAK/STAT signaling in LTM could be through chromatin remodeling.…”

The Drosophila cell adhesion molecule Klingon is required for long-term memory formation and is regulated by Notch

“…T he Notch signaling pathway, which plays critical roles in cell fate specification and differentiation (1), is also important for protein synthesis-dependent long-term memory (LTM) formation (2)(3)(4). Upon ligand binding, the Notch receptor is proteolytically cleaved by presenilin-dependent ␥-secretase (5,6) to release a Notch intracellular domain (NICD), which activates gene expression in the nucleus.…”

“…Upon ligand binding, the Notch receptor is proteolytically cleaved by presenilin-dependent ␥-secretase (5,6) to release a Notch intracellular domain (NICD), which activates gene expression in the nucleus. Over-expression of a dominant-negative Notch, which is defective for NICD function, inhibits LTM formation (3).…”

Notch signaling in the brain: In good and bad times

“…Several papers have confirmed this hypothesis and have shown that Notch has a direct effect on dendritic patterning (Berezovska et al, 1999;Breunig et al, 2007;Redmond et al, 2000;Sestan et al, 1999) and axonal outgrowth (Crowner et al, 2003). We now know, from several studies, that reduction in Notch signaling affects sensory and memory processing across several species (Alberi et al, 2011;Chao et al, 2005;Costa et al, 2003;Ge et al, 2004;Wang et al, 2004). This effect does not appear to be the result of aberrant connectivity, but rather depends on changes in synaptic plasticity (Alberi et al, 2011).…”