Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity.Key words: Cis-inhibition, Delta-like, Signaling diversity, Jagged, Notch, Notch intracellular domain Introduction Cells need to sense cues from their extracellular environment and integrate this information into appropriate developmental or physiological responses. Although there are a number of mechanisms that relay information from the exterior of the cell to the interior, a relatively small set of highly evolutionarily conserved signaling pathways stand out as playing particularly crucial roles in this transmission of information. In this roster of 'elite' intracellular signaling mechanisms are the Wnt pathway, the sonic hedgehog (Shh) pathway, the bone morphogenetic protein/transforming growth factor  (BMP/TGF) pathway, phosphatidylinositol 3-kinase/thymoma viral proto-oncogene (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and, the subject of this review, the Notch signaling pathway. Each of these pathways converts information about the concentration of extracellular ligands into specific transcriptional responses in the nucleus. In most cases, the signaling mechanism consists of the 'core' signaling pathway, i.e. the minimal set of protein components required for transducing the signal, and a more elaborate set of 'auxiliary' proteins, which, in various ways, impinge upon the core pathway and modify the signal but are not intrinsically necessary for relaying the signal.Among these highly conserved pathways (Gazave et al., 2009;Richards and Degnan, 2009), the Notch signaling pathway scores highly with regard to simplicity in molecular design, as it contains only a small number of core signaling components (Fig. 1). Despite this, Notch signaling affects cell differentiation decisions not only across a wide spectrum of metazoan species, but also across a broad range of cell types in a single organism and at different steps during cell lineage progression. The pleiotropic actions of Notch in different cell types and organs have recently been reviewed and are summarized in Table 1. In keeping with its important role in many cell types, the mutation of Notch genes leads to diseases in various organs and tissues (Table 2). These studies highlight the fact that the Notch pathway must be able to elicit appropriate responses in many spatially and temporally...

The Notch signalling pathway is evolutionarily conserved and is crucial for the development and homeostasis of most tissues. Deregulated Notch signalling leads to various diseases, such as T cell leukaemia, Alagille syndrome and a stroke and dementia syndrome known as CADASIL, and so strategies to therapeutically modulate Notch signalling are of interest. Clinical trials of Notch pathway inhibitors in patients with solid tumours have been reported, and several approaches are under preclinical evaluation. In this Review, we focus on aspects of the pathway that are amenable to therapeutic intervention, diseases that could be targeted and the various Notch pathway modulation strategies that are currently being explored.

Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest- and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium, and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results reveal transitions connecting intermediate mesoderm and progenitors of organ primordia, the hematopoietic system, and endothelial subtypes. Unexpectedly, by using a combination of single cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from the nerve-associated Schwann cell precursors similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.

In mice, expression of a missense mutant of Jag1 (Jag1) disrupts bile duct development and recapitulates Alagille syndrome phenotypes in heart, eye, and craniofacial dysmorphology. JAG1 does not bind NOTCH1, but binds NOTCH2, and elicits hypomorphic signaling. This mouse model can be used to study other features of Alagille syndrome and organ development.

Wnts are a family of secreted proteins that regulate multiple steps of neural development and stem cell differentiation.