Snail is required for Delta endocytosis and Notch-dependent activation of<Emphasis Type="Italic"> single-minded</Emphasis> expression

In the Drosophila embryo, the mesectoderm corresponds to a single row of cells abutting the mesoderm. It is specified by the expression of the single-minded (sim) gene. The information that precisely positions the sim-expressing cells along the dorso-ventral axis is incompletely understood. Previous studies have shown that Dorsal and Twist activate sim expression in a large ventral domain, while two negative regulators, Snail (Sna) and Suppressor of Hairless [Su(H)], repress sim expression in the mesoderm and neuroectoderm, respectively. Repression by Su(H) is relieved in the presumptive mesectoderm by Notch signaling. In this paper, we show that Sna also has a positive regulatory function on sim expression in the presumptive mesectoderm. This positive effect of Sna depends on the Su(H)-binding sites within the sim promoter, suggesting that Sna regulates Notch signaling. In addition, we find that Delta is endocytosed together with the extracellular domain of Notch. The endocytosis of Delta is only seen in the mesoderm and requires the activity of the sna and neuralized (neur) genes. Interestingly, the Neur-mediated endocytosis of Delta has recently been shown to be sufficient for the non-autonomous activation of Notch target genes in wing imaginal discs. We therefore propose a novel model in which Sna positions the mesectoderm via its dual regulatory activity. In this model, Sna cell-autonomously represses sim expression in the mesoderm and relieves Su(H)-dependent repression in a cell non-autonomous fashion by promoting the Neur-dependent endocytosis of Delta in the mesoderm.     

Notch activation regulates the segregation and differentiation of rhombomere boundary cells in the zebrafish hindbrain

During segmentation of the vertebrate hindbrain, a distinct population of boundary cells forms at the interface between each segment. Little is known regarding mechanisms that regulate the formation or functions of these cells. We have investigated a potential role of Notch signaling and find that in the zebrafish hindbrain, radical fringe is expressed in boundary cells and delta genes are expressed adjacent to boundaries, consistent with a sustained activation of Notch in boundary cells. Mosaic expression experiments reveal that activation of the Notch/Su(H) pathway regulates cell affinity properties that segregate cells to boundaries. In addition, Notch signaling correlates with a delayed neurogenesis at hindbrain boundaries and is required to inhibit premature neuronal differentiation of boundary cells. These findings reveal that Notch activation couples the regulation of location and differentiation in hindbrain boundary cells. Such coupling may be important for these cells to act as a stable signaling center.     

An activity of Notch regulates JNK signalling and affects dorsal closure in Drosophila.

BACKGROUND: The Drosophila Notch protein is a receptor that controls cell fate during embryonic development, particularly in lateral inhibition, a process that acts on groups of cells that share a particular developmental potential to restrict the number of cells that will adopt that cell fate. The process of lateral inhibition is implemented by the nuclear protein Suppressor of Hairless (Su(H)) and is triggered by the ligand Delta. Recent results have shown that the interaction between Delta and Notch triggers the cleavage of the intracellular domain of Notch which then translocates to the nucleus and binds to Su(H). RESULTS: We find that Notch plays a role in the patterning of the dorsal epidermis of the Drosophila embryo and that this function of Notch is independent of Su(H), requires Notch at the plasma membrane and targets the c-Jun N-terminal kinase (JNK) signalling pathway. Notch mutants show high levels of JNK activity and can rescue the effects of lowered JNK signalling resulting from mutations in the hemipterous and basket genes. Two regions of the intracellular domain of Notch are involved: the Cdc10/ankyrin repeats, which downregulate signalling through the JNK pathway, and a region carboxy-terminal to these repeats, which regulates this negative function. CONCLUSIONS: Our results reveal a novel signalling activity of Notch that does not require its cleavage and acts by modulating signalling through the JNK pathway. In the Drosophila embryo, this activity plays an important role in the morphogenetic movements that drive dorsal closure.     

Perturbation of Notch/Suppressor of Hairless pathway disturbs migration of primordial germ cells in Xenopus embryo

Primordial germ cells (PGCs) in Xenopus embryo are specified in the endodermal cell mass and migrate dorsally toward the future gonads. The role of the signal mediated by Notch and Suppressor of Hairless [Su(H)] was analyzed on the migrating PGCs at the tailbud stage. X‐Notch‐1 and X‐Delta‐1 are expressed in the migrating PGCs and surrounding endodermal cells, whereas X‐Delta‐2 and X‐Serrate‐1 are expressed preferentially in the PGCs. Suppression and constitutive activation of the Notch/Su(H) signaling in the whole endoderm region or selectively in the PGCs resulted in an increase in ectopic PGCs located in lateral or ventral regions. Knocking down of the Notch ligands by morpholino oligonucleotides revealed that X‐Delta‐2 was indispensable for the correct PGC migration. The ectopic PGCs seemed to have lost their motility in the Notch/Su(H) signal‐manipulated embryos. Our results suggest that a cell‐to‐cell interaction via the Notch/Su(H) pathway has a significant role in the PGC migration by regulating cell motility.     

昆虫Notch信号通路研究进展

Notch 信号通路由 Notch 受体、Notch 配体(DSL 蛋白)、CSL[C promoter binding factor-1(CBF1),Suppressor of hairless(Su(H)),Lag-1]转录因子、其他效应子和Notch调节分子构成,在动物组织的发育和器官的细胞命运决定中起着基础性的...     

The role of Suppressor of Hairless in Notch mediated signalling during zebrafish somitogenesis

Suppressor of Hairless (Su(H)) codes for a protein that interacts with the intracellular domain of Notch to activate the target genes of the Delta-Notch signalling pathway. We have cloned the zebrafish homologue of Su(H) and have analysed its function by morpholino mediated knockdown. While there are at least four notch and four delta homologues in zebrafish, there appears to be only one complete Su(H) homologue. We have analysed the function of Su(H) in the somitogenesis process and its influence on the expression of notch pathway genes, in particular her1, her7, deltaC and deltaD. The cyclic expression of her1, her7 and deltaC in the presomitic mesoderm is disrupted by the Su(H) knockdown mimicking the expression of these genes in the notch1a mutant deadly seven. deltaD expression is similarly affected by Su(H) knockdown like deltaC but shows in addition an ectopic expression in the developing neural tube. The inactivation of Su(H) in a fss/tbx24 mutant background leads furthermore to a clear breakdown of cyclic her1 and her7 expression, indicating that the Delta-Notch pathway is required for the creation of oscillation and not only for the synchronisation between neighbouring cells. The strongest phenotypes in the Su(H) knockdown embryos show a loss of all somites posterior to the first five to seven ones. This phenotype is stronger than the known amorphic phenotypes for notch1 (des) or deltaD (aei) in zebrafish, but mimicks the knockout phenotype of RBP-Jkappa gene in the mouse, which is the homologue of Su(H). This suggests that there is some functional redundancy among the Notch and Delta genes. This fact that the first five to seven somites are only weakly affected by Su(H) knockdown indicates that additional genetic pathways may be active in the specification of the most anterior somites.     

Notch steers Drosophila ISNb motor axons by regulating the Abl signaling pathway

The central problem in axon guidance is to understand how guidance signals interact to determine where an axon will grow. Here we investigate a specific axon guidance decision in Drosophila embryos, the sharp inward turn taken by the ISNb motor nerve to approach its muscle targets. We find that this turn requires Notch and its ligand Delta. We show that Delta is expressed on cells adjacent to the ISNb turning point, and we know from previous work that Notch is present on axonal growth cones, suggesting that Delta and Notch might provide a guidance signal to ISNb. To induce the turning of ISNb axons, Notch interacts genetically with multiple components of a signal transduction pathway that includes the Abl tyrosine kinase and its affiliated accessory proteins. In contrast, genetic interaction experiments fail to provide evidence for a major role of the "canonical" Notch/Su(H) signaling pathway in this process. We suggest that the Notch/Abl interaction promotes the turning of ISNb axons by attenuating the Abl-dependent adhesion of ISNb axons to their substratum, thus releasing the axons to respond to attraction from target muscles.