Abstract
BackgroundMammalian Delta-like 1 (Dlk-1) protein shares homology with Notch ligands but lacks a critical receptor-binding domain. Thus it is unclear whether it is able to interact with Notch in vivo. Unlike mammals, Drosophila have a single Notch receptor allowing a simple in vivo assay for mammalian Dlk1 function.ResultsHere we show that membrane-bound DLK1 can regulate Notch leading to altered cellular distribution of Notch itself and inhibiting expression of Notch target genes. The resulting adult phenotypes are indicative of reduced Notch function and are enhanced by Notch mutations, confirming that DLK1 action is antagonistic. In addition, cells expressing an alternative Dlk1 isoform exhibit alterations in cell size, functions previously not attributed to Notch suggesting that DLK1 might also act via an alternative target.ConclusionOur results demonstrate that DLK1 can regulate the Notch receptor despite its atypical structure.
Highlights
Mammalian Delta-like 1 (Dlk-1) protein shares homology with Notch ligands but lacks a critical receptor-binding domain
Our results demonstrate that DLK1 can regulate the Notch receptor despite its atypical structure
Phenotypes from expressing Delta-like 1 (Dlk1) in the Drosophila wing Three different Dlk1 variants were constructed that mimic the different isoforms detected in vivo: secreted form of DLK1 after cleavage (S-Dlk), a secreted form produced by proteolytic cleavage in the extracellular domain, membrane-tethered form of DLK1 (M-Dlk), transmembrane tethered form that lacks the cleavage site, SM-Dlk retains the cleavage site and has the capacity to be both membrane tethered and cleaved (Fig. 1)
Summary
Mammalian Delta-like 1 (Dlk-1) protein shares homology with Notch ligands but lacks a critical receptor-binding domain It is unclear whether it is able to interact with Notch in vivo. The developmental mechanisms leading to these abnormalities are unknown and in particular it is unclear the extent to which this protein has the capability of regulating Notch signalling in vivo, because it lacks an essential extracellular DSL domain common to all known Notch ligands. Notch-ligands are transmembrane proteins that are characterised by a series of EGF-repeats in their extracellular domain, and an N-terminal domain, referred to as the DSL domain (Fig. 1; [6,7,8]) The latter appears to be critical (page number not for citation purposes)
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