Taking it up a Notch


Yikes. Phase 1 is upon us. Less than a month to go, how are you all feeling for it? Personally, I’m not feeling great…but I do have a pretty detailed study plan (see upcoming post for a boards prep plan!) that’s helping to ease my worries. I’m going to be going through some of the important pathways and try to break them down into small nuggets of (hopefully) less painful gen path content.

First up, Notch signaling.

(Taken from Zacharioudaki E and SJ Bray. 2014. Tools and methods for studying Notch signaling in Drosophila melanogaster. Methods 68(1):173-182)

So the Notch gene is a highly conserved, it’s important not only during embryogenesis (developmental decisions including differentiation of tissue types) but in life after-birth too (regulating homeostasis, cancer development, immunity). Essentially, the Notch pathway has three over-arching functions (1) lateral inhibition, (2) lateral induction, and (3) lineage decisions. Lateral inhibition is when a bunch of multipotent cells that are adjacent develop a hierarchy of function so they do not all become the same cell type. On the other hand, lateral induction is when cells of one population determines the outcome of another cell population. Lastly, lineage decisions occur during asymmetric division. This allows daughter cells to develop into different populations of cells depending on Notch pathway modulators and expression.

Although this pathway has many functions, there actually aren’t any second messengers and the mechanism is pretty straightforward (thank goodness). Essentially, a ligand binds to the Notch receptor (a heterodimeric, single-pass transmembrane protein) which releases cleaved Notch into the cytoplasm.  The cleaved Notch is then translocated to the nucleus where it targets certain transcription genes (via interaction with CBF1/Suppressor of Hairless/Lag-1, depending on the species/scenario we’re talking about).  This was a description of canonical Notch signaling, non-canonical exists too and has different ligands and end-points than canonical signaling.

The cool thing about not having second messengers is that there is an important relationship between the amount of ligand that binds Notch and the response the cells undergoes.

As far as test questions seem to go, most of the focus (at least on practice questions) seems to be on the role Notch plays in regulating angiogenesis. So we’ll dive into that.

Both Notch (binding to the Dll4 ligand) and VEGF-A (binding to VEGF2 Receptor, mostly) are critical for angiogenesis and have opposing effects. Notch/Dll4 has inhibitory effects, limiting sprouting of vessels (even to the point of down regulating VEGF2R expression). VEGF expression actually induces Dll4 expression (negative feedback!) which helps to ensure that supporting cells and endothelial cells don’t occlude the new vessels being created.

Typically, VEGF expression is higher in the leading cell than in the cells closer to the sprout (where it’s coming from the parent vessel). There are a lot more details in Zachary and McGavin on the nitty gritty of angiogenesis (EPCs, BMP, PDGF, oh my!), but the information above is the basics on Notch/Dll4 involvement in the process.

Questions, comments, and corrections are welcome in the comments!

References:

  1. Andersson ER, R Sandberg, and U Lendahl. 2011. Notch signaling: simplicity in design, verstaliiy in function. Development. 138:3593-3612
  2. Siekmann AF and ND Lawson. 2007. Notch signalling and the regulation of angiogenesis. Cell Adhesion and Migration. 1:2, 104-106
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