title: Msx genes define a population of mural cell precursors required for head blood vessel maturation.
abstract: Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.
authors.affiliation: Institut Pasteur, Génétique Moléculaire de la Morphogenèse, CNRS URA 2578, Paris, France.
authors.forename: Miguel
authors.initials: M
authors.lastname: Lopes
authors.forename: Olivier
authors.initials: O
authors.lastname: Goupille
authors.forename: Cécile
authors.initials: C
authors.lastname: Saint Cloment
authors.forename: Yvan
authors.initials: Y
authors.lastname: Lallemand
authors.forename: Ana
authors.initials: A
authors.lastname: Cumano
authors.forename: Benoît
authors.initials: B
authors.lastname: Robert
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D005434:Flow Cytometry; D020868:Gene Silencing; D006257:Head / Q000098:blood supply* / Q000196:embryology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051957:MSX1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D009432:Neural Crest / Q000166:cytology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology; D014054:Tomography / Q000379:methods
chemical_list: D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse; D013629:Tamoxifen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9