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Multiple developmental contexts, i.e. Notch
We will be discussing Notch in multiple developmental contexts. The notch pathway is a highly conserved signaling system that plays an important role in cell-cell communication, organization, proliferation, and differentiation. Specifically, notch signaling promotes cellular differentiation and proliferation during various stages of cellular/systemic development. Notch is present in all animals. Mammals have four notch receptors (NOTCH1, NOTCH2, NOTCH3, and NOTCH4). At a high level, notch signaling promotes proliferation. Its activity is inhibited by Numb at least in the context of the neural system, which plays a role in promoting differentiation.

The notch receptor is a transmembrane receptor protein with a large extracellular portion. The large extracellular portion interacts in a calcium-dependent, non-covalent manner with an associated short extracelluar region, a single transmembrane pass, and an intracellular region. The notch pathway works as a gene regulatory mechanism. Ligand binding to the notch receptor induces proteolytic release of the Notch intracellular domain by γ-secretase-like activity. The domain translocates to the nucleus and interacts with CSL (a DNA-binding protein). The result of ligand binding to the notch receptor is transcriptional activation of target genes.


 * Embryogenesis. Notch signaling plays a crucial role in embryonic development through the regulation of anterior-posterior polarity as well as the left-right asymmetry determination in vertebrates. In turn, notch signaling plays a central role in somitogenesis--i.e., the process giving rise to skeletal muscle, cartilage, tendons, endothelial cells, and dermis. Specifically, notch signaling keeps "segmentation clocks" synchronized among developing cells.


 * Central Nervous System. Notch signaling has been found critical for neural progenitor cell (NPC) maintenance and self-renewal in the developing brain. Activation of the notch signaling cascade maintains NPCs in a proliferating state, absent which premature neuronal differentiation and NPC depletion will result. In this context, Numb is a modulator which can antagonize Notch effects resulting in differentiation of NPCs. Recent studies have shown that the notch pathway also plays a crucial role in glial cell specification, development of neurites, and can strongly influence what we perceive as learning and memory.


 * Cardiovascular Development and Angiogenesis. Notch signaling is crucial to cardiovascular formation and morphogenesis in three primary development processes: atrioventricular (AV) canal development (regulating AV boundary formation between the AV canal and the chamber myocardium), myocardial development (regulating ventricular development by its expression in the interventricular septum and endocardial cells of cardiac cushions), and cardiac outflow tract (OFT) development (regulating differentiation of cardiac neural crest cells into vascular cells). Notch signaling also governs selection of endothelial tip and stalk cells during angiogenesis.


 * Endocrine Development. Notch signaling has been found to play a role in the development of the pancreas, intestines (gut), and bone. During stages of development influenced by the notch signaling pathway, the endoderm and ectoderm differentiate into various gastrointestinal epithelial lineages. These lineages include endocrine cells. In this context notch signaling has been shown to regulate the recruitment of endocrine cell types from a common precursor. By contrast, notch has been shown to be a down-regulator in osteoclastogenesis and osteoblastogenesis. Thus, overexpression of Notch signaling inhibits bone morphogenetic osteoblast differentiation.

Question 1: How does the notch signaling pathway play a role in learning and memory?

Question 2: What happens when the notch signaling pathway is dysregulated?

Question 3: What is the role of notch signaling in CD4 and CD8 T cell development?

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