Dll1 haploinsufficiency in adult mice leads to a complex phenotype affecting metabolic and immunological processes.
BACKGROUND
The Notch signaling pathway is an evolutionary conserved signal transduction pathway involved in embryonic patterning and regulation of cell fates during development and self-renewal. Recent studies have demonstrated that this pathway is integral to a complex system of interactions, involving as well other signal transduction pathways, and implicated in distinct human diseases. Delta-like 1 (Dll1) is one of the known ligands of the Notch receptors. The role of the Notch ligands is less well understood. Loss-of-function of Dll1 leads to embryonic lethality, but reduction of Delta-like 1 protein levels has not been studied in adult stage.


RESULTS
Here we present the haploinsufficient phenotype of Dll1 and a missense mutant Dll1 allele (Dll1(C413Y)). Haploinsufficiency leads to a complex phenotype with several biological processes altered. These alterations reveal the importance of Dll1 mainly in metabolism, energy balance and in immunology. The animals are smaller, lighter, with altered fat to lean ratio and have increased blood pressure and a slight bradycardia. The animals have reduced cholesterol and triglyceride levels in blood. At the immunological level a subtle phenotype is observed due to the effect and fine-tuning of the signaling network at the different levels of differentiation, proliferation and function of lymphocytes. Moreover, the importance of the proteolytic regulation of the Notch signaling network emphasized.


CONCLUSIONS
In conclusion, slight alterations in one player of Notch signaling alter the entire organism, emphasizing the fine-tuning character of this pathway in a high number of processes.
Rubio-Aliaga
Isabel
I
Institute of Experimental Genetics, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany.
Przemeck
Gerhard K H
GK
Fuchs
Helmut
H
Gailus-Durner
Valérie
V
Adler
Thure
T
Hans
Wolfgang
W
Horsch
Marion
M
Rathkolb
Birgit
B
Rozman
Jan
J
Schrewe
Anja
A
Wagner
Sibylle
S
Hoelter
Sabine M
SM
Becker
Lore
L
Klopstock
Thomas
T
Wurst
Wolfgang
W
Wolf
Eckhard
E
Klingenspor
Martin
M
Ivandic
Boris T
BT
Busch
Dirk H
DH
Beckers
Johannes
J
Hrabé de Angelis
Martin
M
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002135:Calcium-Binding Proteins; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction
D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D051880:Receptors, Notch