Dkk1 and Dkk2 regulate epicardial specification during mouse heart development.
BACKGROUND
Dkk1 and Dkk2 interact with LRP5 and LRP6 to modulate canonical Wnt signaling during development, and are known to be expressed in the developing heart. However, a loss-of-function mutation in either gene by itself produces no discernable heart phenotype.


METHODS
Using standard husbandry techniques, Dkk1 null and Dkk2 null mouse lines were crossed to create double null embryos, which we examined using histological and immunohistochemical methods.


RESULTS
Double null embryos die perinatally, with a gross head phenotype reminiscent of Dkk1 null embryos. Upon examination of late stage hearts, we observe myocardial defects including ventricular septal defects. At earlier stages, double mutant hearts show myocardial and epicardial hyperplasia. Myocardial hypertrophy is associated with a moderate increase in cell proliferation, but epicardial hypercellularity is not. Rather, the field of proepicardial precursor cells near the liver shows a broadening of expression for the cardiac-specific gap junction protein Connexin 43.


CONCLUSIONS
Dkk1 and Dkk2 both inhibit Wnt signaling to regulate early myocardial proliferation and each can compensate for the loss of the other in that role. Wnt signaling regulates myocardial proliferation in both heart fields at early stages. Additionally, Wnt signaling is sufficient to increase proepicardial specification as measured by Connexin 43 expression, resulting in a hypercellular epicardium and perhaps contributing to later defects.
Phillips
Matthew D
MD
Laboratory of Mammalian Genes and Development, Program in the Genomics of Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, HHS, Bethesda, MD 20892, USA.
Mukhopadhyay
Mahua
M
Poscablo
Cristina
C
Westphal
Heiner
H
D000818:Animals; D049109:Cell Proliferation; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D038081:Organogenesis / Q000235:genetics / Q000502:physiology*; D010496:Pericardium / Q000196:embryology* / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology
C501127:Dkk1 protein, mouse; C405060:Dkk2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D051153:Wnt Proteins