Notch

FIG 22.6  Molecular structure and domain architecture of Notch effectors.

(a) Notch target genes are members of the basic helix–loop–helix (bHLH) class of transcription factors (the insert represents the structure of MyoD). These bind DNA as homoor heterodimers. In Drosophila, Notch induces expression of E(spl), which in turn binds Groucho and leads to suppression of expression of achaete and scute, thereby blocking the neural differentiation pathway. In mammalian cells, Notch induces Hes and Hey, members of the same bHLH family. The C-terminal -WRPW- motif of Hes1 interacts with TLE4, whereas Hey2 binds SIRT1 with its bHLH motif. Together they repress gene

expression. (PDB file: 1MDY) (b) Domain architecture of Notch effector proteins. SIRT1 and TLE4 are histone deacetylases. (Hey1, 2 and HeyL are also known as Hrt1,2,3, Hesr1,2, Herp 2,1 or Chf2,1.)

fate decisions at many stages of the developing embryo. In Drosophila, Notch plays an important role in determining the choice between epidermal and neural development; its activation prevents neurogenesis. More detail on this is given below (see page 720).

Biological functions in humans

In mammals, Hes and Hey have a role in the development of the nervous system, sensory organs (eye, inner ear), pancreas, endocrine cells, and lymphocytes. Hey genes are critical in the cardiovascular system, their dysfunction causing congenital defects, impairments of angiogenic remodelling, and a lack of arterial differentiation.38

Gene cassettes and the Enhancer of Split complex

In Drosophila, genes are often organized by function on the chromosome. The phenomenon of a group of genes, a cassette, having related function and location on the chromosome signifies a so-called gene complex. The Enhancer of Split complex, or E(spl) complex, includes eight genes spread over 50 kilobases on the Drosophila third chromosome. Other examples of Drosophila

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