Abstract
Delta-like (Dll) 1 and Dll4 differently function as Notch ligands in a context-dependent manner. As these ligands share structural properties, the molecular basis for their functional difference is poorly understood. Here, we investigated the superiority of Dll4 over Dll1 with respect to induction of T cell development using a domain-swapping approach in mice. The DOS motif, shared by Notch ligands-except Dll4-contributes to enhancing the activity of Dll for signal transduction. The module at the N-terminus of Notch ligand (MNNL) of Dll4 is inherently advantageous over Dll1. Molecular dynamic simulation revealed that the loop structure in MNNL domain of Dll1 contains unique proline residues with limited range of motion. The Dll4 mutant with Dll1-derived proline residues showed reduced activity. These results suggest that the loop structure-present within the MNNL domain-with a wide range of motion ensures the superiority of Dll4 and uniquely contributes to the triggering of Notch signaling.
Highlights
Notch system is highly conserved from invertebrates to mammals and regulates cell fate decisions during the development of various organs (Bray, 2006; Kopan and Ilagan, 2009)
This system is composed of four Notch receptors (Notch1–4) and four Notch ligands, Delta-like (Dll) 1, Dll4, Jagged (Jag) 1, and Jag2 in mammals; the interaction between these receptors and ligands induces the proteolysis of the Notch receptor, resulting in the translocation of Notch intracellular domain (NICD) into the nucleus, where the binding of NICD with transcription regulators such as Rbpj and MamL1 activates several target gene transcription
Loss-of-function experiments using Notch1-deficient hematopoietic progenitor cells (HPCs) and Dll4-deficient thymic epithelium in vivo clearly demonstrated that the Notch1-Dll4 interaction is pivotal for T lymphopoiesis in the thymus (Radtke et al, 1999; Hozumi et al, 2008b; Koch et al, 2008)
Summary
Notch system is highly conserved from invertebrates to mammals and regulates cell fate decisions during the development of various organs (Bray, 2006; Kopan and Ilagan, 2009). It has been found that T lymphopoiesis can be recapitulated in an in vitro monolayerculture system, in which HPCs bear the exogenous active fragment of Notch or are cultured on Notch ligand-expressing stromal cells (Hozumi et al, 2003; Schmitt and Zuniga-Pflucker, 2002).
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