The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis.
The murine Foxc1/Mf1 and Foxc2/Mfh1 genes encode closely related forkhead/winged helix transcription factors with overlapping expression in the forming somites and head mesoderm and endothelial and mesenchymal cells of the developing heart and blood vessels. Embryos lacking either Foxc1 or Foxc2, and most compound heterozygotes, die pre- or perinatally with similar abnormal phenotypes, including defects in the axial skeleton and cardiovascular system. However, somites and major blood vessels do form. This suggested that the genes have similar, dose-dependent functions, and compensate for each other in the early development of the heart, blood vessels, and somites. In support of this hypothesis, we show here that compound Foxc1; Foxc2 homozygotes die earlier and with much more severe defects than single homozygotes alone. Significantly, they have profound abnormalities in the first and second branchial arches, and the early remodeling of blood vessels. Moreover, they show a complete absence of segmented paraxial mesoderm, including anterior somites. Analysis of compound homozygotes shows that Foxc1 and Foxc2 are both required for transcription in the anterior presomitic mesoderm of paraxis, Mesp1, Mesp2, Hes5, and Notch1, and for the formation of sharp boundaries of Dll1, Lfng, and ephrinB2 expression. We propose that the two genes interact with the Notch signaling pathway and are required for the prepatterning of anterior and posterior domains in the presumptive somites through a putative Notch/Delta/Mesp regulatory loop.
Kume
T
T
Howard Hughes Medical Institute and Department of Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Jiang
H
H
Topczewska
J M
JM
Hogan
B L
BL
D000818:Animals; D001483:Base Sequence; D002319:Cardiovascular System / Q000196:embryology*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D005314:Embryonic and Fetal Development / Q000502:physiology*; D051858:Forkhead Transcription Factors; D006579:Heterozygote; D006720:Homozygote; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D012313:RNA / Q000235:genetics; D051880:Receptors, Notch; D015398:Signal Transduction; D019170:Somites; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D008565:Membrane Proteins; D051880:Receptors, Notch; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein; D012313:RNA