neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development

Abstract

neuralized (neur) is a neurogenic mutant of Drosophila in which many signaling events mediated by the Notch (N) receptor are disrupted. Here, we analyze the role of neur during eye development. Neur is required in a cell-autonomous fashion to restrict R8 and other photoreceptor fates and is involved in lateral inhibition of interommatidial bristles but is not required for induction of the cone cell fate. The latter contrasts with the absolute requirement for Suppressor of Hairless and the Enhancer of split-Complex for cone cell induction. Using gain-of-function experiments, we further demonstrate that ectopic wild-type and truncated Neur proteins can interfere with multiple N-controlled aspects of eye development, including both neur-dependent and neur-independent processes. The Drosophila eye has been a particularly useful model system for studies of cell-cell interactions during formation of a biological pattern. The adult eye consists of some 800 identical ommatidia; each is a complete unit eye containing 20 cells, including 8 photoreceptors and 12 accessory cells. The proper commitment of cell fates in the eye depends on both inhibitory and inductive cell-cell interactions mediated by multiple signaling cascades (1).The Notch (N) receptor is directly involved in the determination of all cell types in the Drosophila eye, in addition to having other functions in controlling growth and polarity of the eye (2-6). N has two opposing functions with regard to early eye neurogenesis. It first promotes R8 photoreceptor differentiation by enhancing expression of the proneural gene for photoreceptors, atonal (7,8). R8 is the first cell fate to differentiate in the eye and is required for recruitment of all other photoreceptors; N clones lack photoreceptors (8,9). N is subsequently involved in restriction of the R8 fate, because a temporally restricted reduction in N function results in the differentiation of clusters of ectopic R8 cells (10). Other experiments performed during larval and pupal development further demonstrated that N is involved in the determination of outer photoreceptors, cone cells, pigment cells, and bristles (2). N thus appears to be required for all stages of ommatidial assembly.A central ''core'' of proteins involved in the N pathway appears to be deployed in a wide variety of settings of N-pathway activity in invertebrates as well as vertebrates (11). The basic scaffold of the N pathway, as it is most often used, appears to be as follows. Interaction of the transmembrane ligand Delta with the transmembrane receptor Notch results in the release of a proteolytic fragment including the intracellular domain of Notch (N IC ) (12)(13)(14). N IC then translocates to the nucleus, where it acts as a coactivator for the sequence-specific DNA-binding protein Suppressor of Hairless [Su(H)] (15, 16). This complex activates transcription of various target genes, which include multiple members of the Enhancer of split-Complex [E(spl)-C] (17-21).Mutations in neuralized (neur) result in a variety of developmenta...

Fat facets and Liquid facets promote Delta endocytosis and Delta signaling in the signaling cells

“…The results of several studies suggest that Neur and Mindbomb are required in the Delta signaling cells to promote Notch activation in the receiving cells (Pavlopoulos et al, 2001;Itoh et al, 2003;Le Borgne and Schweisguth, 2003;Li and Baker, 2004). However, the role of Neur is unclear, as other reports suggest that Neur is required for Delta internalization in the receiving cells, perhaps to bias those cells to become the receivers (Yeh et al, 2000;Lai et al, 2001;Lai and Rubin, 2001a;Lai and Rubin, 2001b).…”

“…The observation that the neur adult eye mutant phenotype resembles that of faf and lqf FDD9 mutants (Fig. 8A) (Lai and Rubin, 2001a) and that neur + is expressed specifically in R-cells that emerge from the furrow (Pavlopoulos et al, 2001; Lai and Rubin, 2001b) Fig. 8B with Fig.…”

“…However, the only specific functions demonstrated for neur + in the eye are a weak requirement in proneural enhancement and lateral inhibition (Lai and Rubin, 2001a;Li and Baker, 2001;Li and Baker, 2004). The observation that the neur adult eye mutant phenotype resembles that of faf and lqf FDD9 mutants (Fig.…”

Neuralized-2 Regulates a Notch Ligand in Cooperation with Mind Bomb-1

“…In Drosophila neurogenesis, Neur acts in a subset of Notch-dependent cell fate decisions, including lateral inhibition, by acting as a ubiquitin ligase and triggering the endocytosis of the ligand Delta (21,23). Mutations in Drosophila neur result in a variety of developmental defects that closely resemble those of Notch mutants and other Notch pathway mutants (20,22,23).…”

FKBP14is an essential gene that regulates Presenilin protein levels and Notch signaling inDrosophila

“…4A,AЈ). Once again, these phenotypes are highly reminiscent of a defect in Notch signaling (Frise et al, 1996;Yaich et al, 1998;Lai and Rubin, 2001). We therefore examined whether FKBP14 was modulating Notch signaling during sense organ patterning by analyzing the effects of FKBP14 loss on the expression of the Notch downstream target E(spl) in third instar presumptive notum tissue.…”