How does Notch signalling mediate lateral inhibition? How is this mechanism thought to regulate timing in neurogenesis

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How does Notch signalling mediate lateral inhibition? How is this mechanism thought to regulate timing in neurogenesis?

In my essay I will be focusing on how Notch signals in the nervous system and how the ligand Delta mediates Notch signalling. In addition, I will also be explaining how various genes also play a role in lateral inhibition via Notch signalling. Furthermore I will explain how this mechanism regulates neurogenesis.

Specification of cells at distinct times and places plays an important role for the production of cellular diversity in the vertebrate nervous system. Molecular signals that influence the generation of distinct cell types are spatially and temporally controlled. So therefore the neural pattern formation needs coordination of signals that provide temporal and spatial coordination. Lateral inhibition is one mechanism by which patterns of different cell types are produced and is a type of intercellular interaction by which a cell adopting the primary fate can inhibit its immediate neighbours from doing the same and therefore they adopt the secondary fate.

Figure 1: This figure shows the process of lateral inhibition where nerve cell inhibits neighbouring epithelial cells from adopting the epithelial fate through Delta-Notch mediated interactions.

The stimulated Notch pathway stops the differentiation of cells and preserves them in a proliferative state. This is known as ‘standard lateral inhibition’. It has been noted that in some cells, activation of the Notch pathway inhibits the neuronal fate and actively influences another fate and this is known as ‘instructive lateral inhibition’. Notch signalling plays a role in the development of multicellular organisms by maintaining the self-renewal potential of some tissues and inducing the differentiation of other tissues. Notch signalling can control stem cell or precursor populations in an undifferentiated state and promote binary cell fate decisions via lateral inhibition. Notch receptors contain a Lin Notch repeat region on the extracellular side and on the intracellular side, there exists a subtransmembrane domain with a subsequent domain of six ankyrin repeats and a domain enriched in proline, glutamine, serine and threonine (Beatus et al, 1998).

 Delta expressing cells can stimulate Notch in surrounding cells which directs them into an alternative developmental pathway. In an equivalence group of cells (scattered cells in a field of undifferentiated cells), one cell acquires a unique fate and communicates to neighbouring cells that they should acquire a different fate. All cells within an equivalence group are in a particular state and contain similar proportions of Notch and Delta. Intrinsic and extrinsic signals results in a new cell state and disrupts this balance by raising the quantities of Delta in one or a few cells. As a result Notch signalling is stimulated, through successive proteolytic cleavages and initiates lateral inhibition.

Experiments conducted on drosophila show that embryos that lack Delta/Notch function have excess neural cells at the expense of the epidermis(Campos-Ortega et al,1995).Notch is a large, single transmembrane domain receptor protein where ligands such as serrate as well as Delta act on(Cornell et al,2005).

The ligand Delta, a transmembrane protein which has a number of EGF repeats on the extracellular side binds Notch receptor and cleavage of the intracellular domain of Notch occurs by an extracellular enzyme. This produces a Notch intracellular domain (NICD/Notch 1C) where it is further processed by presenilin, ubiquitinylated and is transported into the nucleus. It then binds to RBPJK, a CSL transcription factor and plays a role in upregulating the bHLH gene, Hes1.This gene then in turn suppresses MASH1 expression and various other bHLH proneural genes which keep the cells in an undifferentiated state. These proneural genes are part of the family of the achaete-scute complex (A-Sc) and the products of the A-Sc genes are basic helix-loop-helix (bHLH) transcription factors. These factors have an upstream role where they induce the expression of genes contained within the proneural cluster. When cells become committed to a neural fate, the level of A-Sc proteins rises and the surrounding neighbours within the cluster decreases proving that these factors also have a downstream role. The increased expression of A-Sc genes in the nascent neural cell is transient which also reflects the Delta expression (Lewis et al, 1996). A-Sc is expressed in drosophila and MASH is expressed in mammals and so A-Sc/MASH positively controls Delta expression (Beatus et al, 1998).Cells which express Delta will promote stronger expression of E (spl) in surrounding cells via the Notch pathway. These neighbouring cells with raised levels of E (spl) /Hes will inhibit A-Sc/MASH expression and also of Delta. But after a certain time these cells impair their ability to signal and convert into receiving signals.

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The signalling cells which started off having high levels of Delta in contrast to neighbouring cells will receive fewer stimuli of their Notch receptors due to low levels of Delta on neighbouring cells. This results in low levels of E (spl) /Hes which raises A-Sc/MASH activity and Delta expression.

Figure 2: This diagram shows that in embryos cultured for 24 hours in control (A, C, E) demonstrate expression of cHes5 genes in neural tube, in the anterior and posterior domains of the otic cup. When they are exposed to DAPT, an inhibitor of Notch signalling and a gamma secretase ...

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