UNSW Embryology

Molecular Development - Notch

© Dr Mark Hill (2008)

Acknowledgements

Introduction

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Notch signaling has roles in development and differentiation at different times in many different systems in the embryo. In mammals, there have been identified 4 Notch receptors (Notch 1-4) and five receptors ligands (Jagged1 and 2, and Delta-like 1, 3 and 4).

Notch signaling is involved in the cell-cell signaling processs of lateral inhibition. Lateral inhibition is where selected cells have a particular differentiation fate and through notch signalling inhibit direct neighbours from that differentiation fate.

Notch signaling has also been implicated in tumorogenic mechanisms of tumor cell migration and invasion.

Notch can be proteolytically cleaved by gamma-Secretase (which also cleaves amyloid precursor protein, APP).

Page Links: Introduction | Some Recent Findings | Systems | OMIM Entry Notch | Bookshelf References | Human Notch Map | Signaling Factors | WWW Links | References | Glossary

Some Recent Findings

Nelson BR, Reh TA. Relationship between delta-like and proneural bHLH genes during chick retinal development. Dev Dyn. 2008 Apr 24; (More? Eye Notes)

"Notch signaling in the retina maintains a pool of progenitor cells throughout retinogenesis. ...Notch ligands Delta-like gene family Dll4 matched the pattern of neural differentiation. By contrast, Dll1 was primarily expressed in progenitor cells."

Holderfield MT, Hughes CC. Crosstalk between vascular endothelial growth factor, notch, and transforming growth factor-beta in vascular morphogenesis. Circ Res. 2008 Mar 28;102(6):637-52. Review (More? Cardiovascular System - Blood Vessels)

Scoville DH, Sato T, He XC, Li L. Current view: intestinal stem cells and signaling. Gastroenterology. 2008 Mar;134(3):849-64. Review (More? Gastrointestinal Tract Notes)

Watanabe Y, Kokubo H, Miyagawa-Tomita S, Endo M, Igarashi K, Aisaki KI, Kanno J, Saga Y. Watanabe Y, Kokubo H, Miyagawa-Tomita S, Endo M, Igarashi K, Aisaki KI, Kanno J, Saga Y. Activation of Notch1 signaling in cardiogenic mesoderm induces abnormal heart morphogenesis in mouse. Development. 2006 May;133(9):1625-34. (More? Heart Notes)

"...Our present study thus indicates that the Notch1 signaling pathway plays a suppressive role both in AV myocardial differentiation and the maturation of the ventricular myocardium."

Systems

The following develpmental systems have been shown to be reulated at some stage by Notch signaling. (Links are to systems notes)

Mesenchyme Development - (connective tissue) zinc finger protein 64 (Zfp64) is a coactivator of Notch1 which suppresses myogenic and promotes osteoblastic differentiation. (PMID:18430783) Another paper shows that Notch signaling in osteoblasts impairs osteoblastogenesis by inhibiting the Wnt/beta-catenin pathway (PMID:18420737)

Somite segmentation - lunatic fringe (Lfng) blocking Notch cleavage blocks the segmentation clock.

Eye Development - maintains a pool of progenitor cells throughout retinogenesis, transient inactivation of Notch signaling synchronizes progenitor cell differentiation (PMID:17280659) (Eye Notes)

Blood Vessel (Cardiovascular System - Blood Vessels)

Heart (Heart Notes)

Gastrointestinal Tract (Gastrointestinal Tract Notes)

Immune System - specifys T cell fate and promotes early stages of T cell differentiation. (PMID:18434124)

Eye Signaling Pathway

Retinal Progenitor Cells

Ascl1

↓

Dll1/4

↓

Notch

Mesenchyme Signaling Pathway

Mesenchymal Cells

Runx2

↓

Zfp64

↓

Notch1

↓

osteoblastic differentiation

Neural Signaling Pathway

lunatic fringe upregulates Delta-1 expression

Signaling Pathway

TGF-alpha

↓

Notch (increases)

Notch Structure

Transmembrane protein

extracellular domain - multiple epidermal growth factor-like (EGF) repeats

intracellular domain - multiple different domain types

Delta-like - a single-pass transmembrane protein

intracellular domain - C-terminal PDZ binding motif

Database Entry Links

Genbank | Swiss-protein

Human Genbank Entries

LocusID Symbol Description Position Links 4851 NOTCH1 Notch (Drosophila) homolog 1 (translocation-associated) 9q34.3 4853 NOTCH2 Notch (Drosophila) homolog 2 1p13-p11 4854 NOTCH3 Notch (Drosophila) homolog 3 19p13.2-p13.1 4855 NOTCH4 Notch (Drosophila) homolog 4 6p21.3

Help

Locus Link Help Page

Link code PubMed OMIM RefSeq GenBank UniGene Variation

top of page

Swiss-Protein NiceProt View

 

OMIM Database

 

 

Bookshelf References

Developmental Biology (6th ed.) Gilbert, Scott F. Sunderland (MA): Sinauer Associates, Inc. (c2000)

Image: Homology of process in the formation of the anterior-posterior axes in Drosophila and chick appendages

Image: The Hedgehog signal transduction pathway

Image: The Hedgehog signal transduction pathway

Molecular Biology of the Cell (4th ed.) Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York: Garland Publishing (c2002)

Image: dorsoventral axis

Image: lung morphogenesis

Image: chick limb development

Image: limb patterning molecules

Human Notch Map

The image below shows the regional location of the human Notch 1 gene homolog on chromosome 9q34.3.

Signaling Factors

Signaling during development, though complex, can also be grouped into a few specific classes. These mechanisms have also been listed and described briefly on Signaling Mechanisms Introduction page.

Bone Morphogenic Protein (BMP) | Engrailed (En) | Fibroblast Growth Factor (FGF) | Hedgehog (HH) | Homeobox genes (Hox) | Laminin | MyoD | Nanog | Nodal | Paired Box (Pax) | PItuitary-specific Transcription factor (Pit) | Retinoic Acid (RA) | Snail | | Sonic Hedgehog (SHH) | SRY | T-Box genes | Transforming Growth Factor-beta (TGF-b) | Olig | Vascular Endothelial Growth Factor (VEGF) | Wnt7a