Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo.
The Notch ligands Dll1 and Dll3 are coexpressed in the presomitic mesoderm of mouse embryos. Despite their coexpression, mutations in Dll1 and Dll3 cause strikingly different defects. To determine if there is any functional equivalence, we replaced Dll1 with Dll3 in mice. Dll3 does not compensate for Dll1; DLL1 activates Notch in Drosophila wing discs, but DLL3 does not. We do not observe evidence for antagonism between DLL1 and DLL3, or repression of Notch activity in mice or Drosophila. In vitro analyses show that differences in various domains of DLL1 and DLL3 individually contribute to their biochemical nonequivalence. In contrast to endogenous DLL1 located on the surface of presomitic mesoderm cells, we find endogenous DLL3 predominantly in the Golgi apparatus. Our data demonstrate distinct in vivo functions for DLL1 and DLL3. They suggest that DLL3 does not antagonize DLL1 in the presomitic mesoderm and warrant further analyses of potential physiological functions of DLL3 in the Golgi network.
Geffers
Insa
I
Institut für Molekularbiologie, Medizinische Hochschule Hannover, Hannover, Germany.
Serth
Katrin
K
Chapman
Gavin
G
Jaekel
Robert
R
Schuster-Gossler
Karin
K
Cordes
Ralf
R
Sparrow
Duncan B
DB
Kremmer
Elisabeth
E
Dunwoodie
Sally L
SL
Klein
Thomas
T
Gossler
Achim
A
D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D002135:Calcium-Binding Proteins; D002460:Cell Line; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000196:embryology; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019170:Somites / Q000033:anatomy & histology / Q000502:physiology; D014018:Tissue Distribution; D014921:Wings, Animal / Q000033:anatomy & histology / Q000196:embryology
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; C511877:Dll3 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D020033:Protein Isoforms; D051880:Receptors, Notch; D011993:Recombinant Fusion Proteins