The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis

• Published in: Genes & development Vol. 15; no. 18; pp. 2470 - 2482
• Main Authors: Kume, T, Jiang, H, Topczewska, J M, Hogan, B L
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 15.09.2001
• Subjects: Animals; Base Sequence; Cardiovascular System - embryology; Delta protein; Dll1 gene; DNA Primers; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Embryonic and Fetal Development - physiology; ephrinB2 gene; forkhead protein; Forkhead Transcription Factors; Foxc1 gene; Foxc1 protein; Foxc2 gene; Foxc2 protein; Hes5 gene; Heterozygote; Homozygote; Lfng gene; Membrane Proteins - metabolism; Mesp protein; Mesp1 gene; Mesp2 gene; Mf1 gene; Mfh1 gene; Mice; Mice, Mutant Strains; Notch protein; Notch1 gene; paraxis gene; Receptors, Notch; Research Paper; RNA - genetics; Signal Transduction; Somites; somitogenesis; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; winged protein
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.907301

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.