Notch transmembrane receptors bind to trans membrane ligands of the DSL (Delta/Serrate/ LAG-2) family, which requires cell-to-cell con tact (juxtacrine signaling) for signaling to occur. In mammals, there are four Notch family members and five transmembrane ligands (lagged 1 and 2 and Delta 1 to 3). Binding of one of these proteins to a Notch receptor causes a conformational change in the Notch protein such that part of it on the cytoplasmic side of the membrane is cleaved. The pathway is very straightforward in that there are no second messengers involved. Thus, the cleaved portion of the protein enters the nucleus directly and binds to a DNA-binding protein that normally represses transcription of Notch target genes. Binding of Notch removes the inhibitory activity of the repressor and permits activation of downstream genes (Fig. 1).

Fig1. Drawing illustrating signaling via the Notch pathway. Notch receptors located on one cell bind a ligand from the DSL family [Jagged or Serrate] that are located on an adjacent cell [juxtacrine signaling], and this receptor—ligand interaction activates a proteolytic enzyme that cleaves the Notch protein to pro— duce the activated membrane anchored Notch extracellular truncation [NEXT]. NEXT is then cleaved by an intracellular secretase enzyme that results in the release of Notch intracellular domain [NICD] that represents the active signaling portion of the original Notch receptor. NICD translocates directly to the nucleus where it binds to transcription repressors and removes their inhibitory activity on downstream target genes of the Notch pathway.

Notch signaling is involved in cell proliferation, apoptosis, and epithelial to mesenchymal transitions. It is especially important in neuronal differentiation, blood vessel formation and specification (angiogenesis), somite segmentation, pancreatic B-cell development, B- and T-cell differentiation in the immune system, development of inner ear hair cells, and septation of the outflow tract of the heart. Mutations in JAG1 or NOTCH2 cause Alagille syndrome characterized by cardiac outflow tract defects as well as skeletal, ocular, renal, and hepatic abnormalities. JAG1 mutations have also been linked to cases of tetralogy of Fallot (a cardiac outflow tract defect).

مواضيع ذات صلة

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تكون وتمايز الجسيدات

تشكل العصيبة عند البرمائيات

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العصيبة وتشكل الجسيدات

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التحريض الأولي العصبي

الأديم المتوسط للجنين الفتي

إفراز المولد خارج الخلوي في المراحل المبكرة من تكون الأجنة