Dataset Information

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo.

ABSTRACT: Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool). In other processes, however, they appear to act differently (e.g. maintenance of foetal arterial identity) raising the questions of how similar DLL1 and DLL4 really are and which mechanism causes the apparent context-dependent divergence. By analysing mice that conditionally overexpress DLL1 or DLL4 from the same genomic locus (Hprt) and mice that express DLL4 instead of DLL1 from the endogenous Dll1 locus (Dll1Dll4ki), we found functional differences that are tissue-specific: while DLL1 and DLL4 act redundantly during the maintenance of retinal progenitors, their function varies in the presomitic mesoderm (PSM) where somites form in a Notch-dependent process. In the anterior PSM, every cell expresses both Notch receptors and ligands, and DLL1 is the only activator of Notch while DLL4 is not endogenously expressed. Transgenic DLL4 cannot replace DLL1 during somitogenesis and in heterozygous Dll1Dll4ki/+ mice, the Dll1Dll4ki allele causes a dominant segmentation phenotype. Testing several aspects of the complex Notch signalling system in vitro, we found that both ligands have a similar trans-activation potential but that only DLL4 is an efficient cis-inhibitor of Notch signalling, causing a reduced net activation of Notch. These differential cis-inhibitory properties are likely to contribute to the functional divergence of DLL1 and DLL4.

SUBMITTER: Preuße K

PROVIDER: S-EPMC4482573 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo.

Preuße Kristina K Tveriakhina Lena L Schuster-Gossler Karin K Gaspar Cláudia C Rosa Alexandra Isabel AI Henrique Domingos D Gossler Achim A Stauber Michael M

PLoS genetics 20150626 6

Notch signalling is a fundamental pathway that shapes the developing embryo and sustains adult tissues by direct communication between ligand and receptor molecules on adjacent cells. Among the ligands are two Delta paralogues, DLL1 and DLL4, that are conserved in mammals and share a similar structure and sequence. They activate the Notch receptor partly in overlapping expression domains where they fulfil redundant functions in some processes (e.g. maintenance of the crypt cell progenitor pool). ...[more]

PMID: 26114479

Similar Datasets

Project description:Reports have suggested that the two Notch ligands, Dll1 and Dll4, are indispensable to maintain the homeostasis of the intestinal epithelium. However, within the intestinal epithelium, the precise distribution of the cells that express those ligands at the protein level remains largely unknown. Here, we show a series of immunohistochemical analysis through which we successfully identified mice intestinal epithelial cells (IECs) that endogenously express Dll1 or Dll4. Results showed that Dll1-positive (Dll1+ve) IECs reside exclusively within the crypt, whereas Dll4-positive (Dll4+ve) IECs can locate both in the crypt and in the villus of the small intestine. Also in the colon, Dll1+ve IECs resided at the lower part of the crypt, whereas Dll4+ve IECs resided at both upper and lower part of the crypt, including the surface epithelium. Both Dll1+ve and Dll4+ve IECs were ATOH1-positive, but Hes1-negative cells, and located adjacent to Hes1-positive cells within the crypts. A sub-population of both Dll1+ve and Dll4+ve IECs appeared to co-express Muc2, but rarely co-expressed other secretory lineage markers. However, as compared to Dll1+ve IECs, Dll4+ve IECs included larger number of Muc2-postive IECs, suggesting that Dll4 is more preferentially expressed by goblet cells. Also, we identified that Dll4 is expressed in the Paneth cells of the small intestine, whereas Dll1 and Dll4 is expressed in the c-kit-positive IECs of the colon, indicating that Dll1+ve and Dll4+ve IECs may contribute to constitute the intestinal stem cell niche. Compared to the normal colon, analysis of DSS-colitis showed that number of Dll1+ve IECs significantly decrease in the elongated crypts of the inflamed colonic mucosa. In sharp contrast, number of Dll4+ve IECs showed a significant increase in those crypts, which was accompanied by the increase in number of Hes1-positive IECs. Those Dll4+ve IECs were mostly found adjacent to the Hes1-positive IECs, suggesting that Dll4 may act as a major Notch ligand in the crypts of the inflamed colonic mucosa. Our results illustrate distinct expression patterns of Dll1 and Dll4 within the intestinal epithelium, and suggest that these two ligands may have different roles in normal and inflamed mucosa.

Dataset Information

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo.

Publications

Context-Dependent Functional Divergence of the Notch Ligands DLL1 and DLL4 In Vivo.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets