Context-Dependent Sensitivity to Mutations Disrupting the Structural Integrity of Individual EGF Repeats in the Mouse Notch Ligand DLL1

Genetics
Karin Schuster-GosslerA Gossler

Abstract

The highly conserved Notch-signaling pathway mediates cell-to-cell communication and is pivotal for multiple developmental processes and tissue homeostasis in adult organisms. Notch receptors and their ligands are transmembrane proteins with multiple epidermal-growth-factor-like (EGF) repeats in their extracellular domains. In vitro the EGF repeats of mammalian ligands that are essential for Notch activation have been defined. However, in vivo the significance of the structural integrity of each EGF repeat in the ligand ectodomain for ligand function is still unclear. Here, we analyzed the mouse Notch ligand DLL1. We expressed DLL1 proteins with mutations disrupting disulfide bridges in each individual EGF repeat from single-copy transgenes in the HPRT locus of embryonic stem cells. In Notch transactivation assays all mutations impinged on DLL1 function and affected both NOTCH1 and NOTCH2 receptors similarly. An allelic series in mice that carried the same point mutations in endogenous Dll1, generated using a mini-gene strategy, showed that early developmental processes depending on DLL1-mediated NOTCH activation were differently sensitive to mutation of individual EGF repeats in DLL1. Notably, some mutations affected only somi...Continue Reading

References

Aug 20, 1996·Proceedings of the National Academy of Sciences of the United States of America·S K BronsonO Smithies
Apr 17, 1997·Nature·M Hrabĕ de AngelisA Gossler
May 1, 1997·Molecular and Cellular Biology·S MinoguchiT Honjo
Jun 22, 1999·Developmental Biology·B G BruneauC E Seidman
Jan 15, 2000·Current Topics in Developmental Biology·H H Arnold, T Braun
Feb 7, 2001·Human Molecular Genetics·J D MorrissetteN B Spinner
May 31, 2002·The Journal of Biological Chemistry·Vladislav M PaninRobert S Haltiwanger
Jan 16, 2003·Cell·Tetsuya Okajima, Kenneth D Irvine
Apr 17, 2003·Proceedings of the National Academy of Sciences of the United States of America·Shaolin Shi, Pamela Stanley
May 6, 2003·Genes & Development·Luke T KrebsThomas Gridley
Dec 4, 2004·Structure·Sophie HambletonA Kristina Downing
Mar 12, 2005·BMC Developmental Biology·Lee-Peng MokCedric Wesley
Jul 5, 2005·The Journal of Biological Chemistry·Aiguo XuKenneth D Irvine
Dec 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Karin Schuster-GosslerAchim Gossler
Aug 1, 2007·The Journal of Cell Biology·Insa GeffersAchim Gossler
Oct 30, 2007·Current Opinion in Structural Biology·Pamela Stanley
Feb 26, 2008·The Journal of Biological Chemistry·Jemima CordlePenny A Handford
Jul 29, 2008·Nature Structural & Molecular Biology·Jemima CordlePenny A Handford
Mar 31, 2010·Nucleic Acids Research·Joana A VidigalBernhard G Herrmann
May 4, 2010·Human Mutation·Robert C BauerNancy B Spinner
Aug 11, 2011·Development·Emma R AnderssonUrban Lendahl
Dec 2, 2011·Cellular and Molecular Life Sciences : CMLS·Reena SinghVincent M Christoffels
Feb 7, 2012·Seminars in Cell & Developmental Biology·Andrea L PentonNancy B Spinner
Feb 7, 2012·Seminars in Cell & Developmental Biology·Abdiwahab A MusseGerry Weinmaster
Feb 14, 2012·Seminars in Cell & Developmental Biology·Chandramouli R ChillakuriPenny A Handford
Jun 5, 2012·Developmental Cell·Laurence Meloty-KapellaGerry Weinmaster
Aug 30, 2012·Nature Methods·Caroline A SchneiderKevin W Eliceiri
Jul 11, 2013·The Journal of Biological Chemistry·Marie Blanke AndrawesStephen C Blacklow
Feb 24, 2015·Science·Vincent C LucaK Christopher Garcia

❮ Previous
Next ❯

Citations

Sep 18, 2016·Journal of Cellular Biochemistry·Ledi LiuMotoyuki Itoh
Jun 18, 2017·Cell and Tissue Research·Runrui ZhangVerdon Taylor
Jul 6, 2016·Therapeutic Advances in Respiratory Disease·Dandan ZongPing Chen
Sep 30, 2021·BMC Research Notes·Karin Schuster-GosslerAchim Gossler

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.