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Notch signaling in embryogensis
The Notch signaling pathway plays an important role in cell-cell communication, and further regulates embryonic development. Early studies in C. elegans indicate that Notch signaling has a major role in the induction of mesoderm and cell fate determination.

Notch signaling in embryo polarity
Notch signaling is required in the regulation of polarity. For example, mutation experiments have shown that loss of Notch signaling causes abnormal anterior-posterior polarity in somites. Also, Notch signaling is required during left-right asymmetry determination in vertebrates.

Notch signaling in somitogenesis
Notch signaling is central to somitogenesis. In 1995, Notch1 was shown to be important for coordinating the segmentation of somites in mice. Further studies identified the role of Notch signaling in the segmentation clock. These studies hypothesized that the primary function of Notch signaling does not act on an individual cell, but coordinates cell clocks and keep them synchronized. This hypothesis explained the role of Notch signaling in the development of segmentation and has been supported by experiments in mice and zebrafish. Experiments with Delta1 mutant mice that show abnormal somitogenesis with loss of anterior/posterior polarity suggest that Notch signaling is also necessary for the maintenance of somite borders.

Notch signaling in central nervous system development and function
Early findings on Notch signaling in Central Nervous System (CNS) development were mainly performed in Drosophila with mutagenesis experiments. For example, the finding that an embryonic lethal phenotype in Drosophila was associated with Notch dysfunction indicated that Notch mutations can lead to the failure of neural and epidermal cell segregation in early Drosophila embryos. In the past decade, advances in mutation and knockout techniques allowed research on the Notch signaling pathway in mammalian models, especially rodents.

The Notch signaling pathway was mainly found to be critical for neural progenitor cell (NPC) maintenance and self-renewal. In recent years, other functions of the Notch pathway have also been found, including glial cell specification, neurites development as well as learning and memory.

Notch signaling in neuron cell differentiation
The Notch pathway is essential for maintaining NPCs in the developing brain. Activation of the pathway is sufficient to maintain NPCs in a proliferating state, whereas loss‑of‑function mutations in the critical components of the pathway cause precocious neuronal differentiation and NPC depletion. Modulators of the Notch signal, e.g., the Numb protein are able to antagonize Notch effects, resulting in the halting of cell cycle and differentiation of NPCs. In this way, Notch signaling controls NPC self-renewal as well as cell fate specification.

Notch signaling in neurite development
In vitro studies show that Notch can influence neurite development. In vivo, deletion of the Notch signaling modulator, Numb, disrupts neuronal maturation in the developing cerebellum, whereas deletion of Numb disrupts axonal arborization in sensory ganglia. Although the mechanism underlying this phenomena is not clear, together these findings suggest Notch signaling might be crucial in neuronal maturation.

Notch signaling in gliogenesis
In gliogenesis, Notch appears to have an instructive role which can directly promote the differentiation of many glial cell subtypes. For example, activation of Notch signaling in the retina favors the generation of Muller glia cells at the expense of neurons, whereas reduced Notch signaling induces production of ganglion cells, causing a reduction in the number of Muller glia.

Notch signaling in adult brain function
In addition to developmental functions, Notch proteins and ligands are expressed in cells of the adult nervous system, suggesting a role in CNS plasticity throughout life. Adult mice heterozygous for mutations in either Notch1 or Cbf1 have deficits in spatial learning and memory. Similar results are seen in experiments with presenilins1 and 2, which mediate the Notch intramembranous cleavage. Specifically, conditional deletion of presenilins at 3 weeks after birth in excitatory neurons causes learning and memory deficits, neuronal dysfunction, and gradual neurodegeneration.

Notch signaling in cardiovascular development
The Notch signaling pathway is a critical component of cardiovascular formation and morphogenesis in both development and disease. It is required for the selection of endothelial tip and stalk cells during sprouting angiogenesis.

Notch signaling in cardiac development
Notch signal pathway plays a crucial role in at least three cardiac development processes: Atrioventricular canal development, myocardial development as well as cardiac outflow tract (OFT) development.

1. Notch signaling in atrioventricular (AV) canal development
Studies have revealed that both loss- and gain-of-function of the Notch pathway results in defects in AV canal development. In addition, the Notch target genes Hey1 and Hey2 are involved in restricting the expression of two critical developmental regulator proteins, BMP2 and Tbx2, to the AV canal.
 * AV boundary formation
 * Notch signaling can regulate the atrioventricular boundary formation between the AV canal and the chamber myocardium.


 * AV epithelial-mesenchymal transition (EMT)
 * Notch signaling is also important for the process of AV EMT, which is required for AV canal maturation. After the AV canal boundary formation, a subset of endocardial cells lining the AV canal are activated by signals emanating from the myocardium and by interendocardial signaling pathways to undergo EMT. Notch1 deficiency results in defective induction of EMT. Very few migrating cells are seen and these lack mesenchymal morphology. Notch may regulate this process by activating matrix metalloproteinase2 (MMP2) expression, or by inhibiting vascular endothelial (VE)-cadherin expression in the AV canal endocardium while suppressing the VEGF pathway via VEGFR2. In RBPJk/CBF1-targeted mutants, the heart valve development is severely disrupted, presumably because of defective endocardial maturation and signaling.

2. Notch signaling in ventricular development

 * Some studies in Xenopus and in mouse embryonic stem cells indicate that cardiomyogenic commitment and differentiation require Notch signaling inhibition. Active Notch signaling is required in the ventricular endocardium for proper trabeculae development subsequent to myocardial specification by regulating BMP10, NRG1, and EphrinB2 expression.


 * The downstream effector of Notch signaling, Hey2, was also demonstrated to be important in regulating ventricular development by its expression in the interventricular septum and the endocardial cells of the cardiac cushions. Cardiomyocyte and smooth muscle cell–specific deletion of Hey2 results in impaired cardiac contractility, malformed right ventricle, and ventricular septal defects.

3. Notch signaling in ventricular outflow tract development

 * During development of the aortic arch and the aortic arch arteries, the expression pattern of the Notch receptors, ligands, and target genes have a unique pattern. When the Notch pathway was blocked, the induction of vascular smooth muscle cell marker expression failed to occur, suggesting that Notch is involved in the differentiation of cardiac neural crest cells into vascular cells during outflow tract development.

Notch signaling in angiogenesis
Endothelial cells use the Notch signaling pathway to coordinate cellular behaviors during the blood vessel sprouting that occurs in angiogenesis.

Activation of Notch takes place primarily in “connector” cells and cells that line patent stable blood vessels through direct interaction with the Notch ligand, Delta-like ligand 4 (Dll4), which is expressed in the endothelial tip cells. VEGF signaling, which is an important factor for migration and proliferation of endothelial cells, can be downregulated in cells with activated Notch signaling by lowering the levels of Vegf receptor transcript. Zebrafish embryos lacking Notch signaling exhibit ectopic and persistent expression of the zebrafish ortholog of VEGF3, flt4, within all endothelial cells, while Notch activation completely represses its expression.

Notch signaling may be used to control the sprouting pattern of blood vessels during angiogenesis. When cells within a patent vessel are exposed to VEGF signaling, only a restricted number of them initiate the angiogenic process. Vegf is able to induce Dll4 expression. In turn, Dll4 expressing cells down‑regulate Vegf receptors in neighboring cells through activation of Notch, thereby preventing their migration into the developing sprout. Similarly, during the sprouting process itself, the migratory behavior of connector cells must be limited to retain a patent connection to the original blood vessel.

Notch signaling in endocrine development
During development, definitive endoderm and ectoderm differentiates into several gastrointestinal epithelial lineages, including endocrine cells. Many studies have indicated that Notch signaling has a major role in endocrine development.

Notch signaling in pancreatic development
The formation of the pancreas from endoderm begins in early development. The expression of elements of the Notch signaling pathway have been found in the developing pancreas, suggesting Notch signaling is important in pancreatic development. Evidence suggests Notch signaling regulates the progressive recruitment of endocrine cell types from a common precursor, acting through two possible mechanisms. One is the “lateral inhibition,” which specifies some cells for a primary fate but others for a secondary fate among cells that have the potential to adopt the same fate. Lateral inhibition is required for many types cell fate determination. Here, it could explain the dispersed distribution off endocrine cells within pancreatic epithelium. A second mechanism is “suppressive maintenance,” which explains the role of Notch signaling in pancreas differentiation. Fibroblast growth factor10 is thought to be important in this activity, but the details are unclear.

Notch signaling and intestinal development
The role of Notch signaling in the regulation of gut development has been indicated in several reports. Mutations in elements of the Notch signaling pathway affect the earliest intestinal cell fate decisions during zebrafish development. Transcriptional analysis and gain of function experiments revealed that Notch signaling targets Hes1 in the intestine and regulates a binary cell fate decision between adsorptive and secretory cell fates.

Notch signaling and bone development
Early in vitro studies have found the Notch signaling pathway functions as down-regulator in osteoclastogenesis and osteoblastogenesis. Notch1 is expressed in the mesenchymal condensation area and subsequently in the hypertrophic chondrocytes during chondrogenesis. Overexpression of Notch signaling inhibits bone morphogenetic protein2-induced osteoblast differentiation. Overall, Notch signaling has a major role in the commitment of mesenchymal cells to the osteoblastic lineage and provides a possible therapeutic approach to bone regeneration.