Transforming growth factor beta-SMAD2 signaling regulates aortic arch innervation and development.
Aortic arch interruptions in humans and animal models are mainly caused by aberrant development of the fourth pharyngeal arch artery. Little is known about the maturation of this vessel during normal and abnormal development, which is the subject of this study. Tgfbeta2 knockout mice that present with fourth artery defects have been associated with defective neural crest cell migration. In this study, we concentrated on pharyngeal arch artery development during developmental days 12.5 to 18.5, focusing on neural crest cell migration using a Wnt1-Cre by R26R neural crest cell reporter mouse. Fourth arch artery maturation was studied with antibodies directed against smooth muscle alpha-actin and neural NCAM-1 and RMO-270. For diminished transforming growth factor beta (TGF-beta) signaling, SMAD2 and fibronectin have been analyzed. Neural crest migration and differentiation into smooth muscle cells is unaltered in mutants, regardless of the cardiovascular defect found; however, innervation of the fourth arch artery is affected. Absent staining for nuclear SMAD2, NCAM-1, and RMO-270 in the fourth artery in mutant coincides with severe defects of this segment. Likewise, fibronectin expression is diminished in these cases. From these data we conclude the following: (1) neural crest cell migration is not a common denominator in cardiovascular defects of Tgfbeta2-/- mice; (2) fourth arch artery maturation is a complex process involving innervation; and (3) TGF-beta2 depletion diminishes SMAD2-signaling in the fourth arch artery and coincides with reduced vascular NCAM-1 expression and neural innervation of this artery. We hypothesize that disturbed maturation of the fourth pharyngeal arch artery, and especially abrogated vascular innervation, will result in fourth arch interruptions.
Molin
Daniel G M
DG
Department of Anatomy and Embryology, Leiden University Medical Center, PO Box 9602, 2300 RC Leiden, The Netherlands.
Poelmann
Robert E
RE
DeRuiter
Marco C
MC
Azhar
Mohamad
M
Doetschman
Thomas
T
Gittenberger-de Groot
Adriana C
AC
D000015:Abnormalities, Multiple / Q000196:embryology* / Q000235:genetics; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities / Q000196:embryology* / Q000294:innervation*; D015415:Biomarkers; D019002:CD56 Antigen / Q000096:biosynthesis; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000502:physiology*; D004310:Double Outlet Right Ventricle / Q000196:embryology / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology*; D009432:Neural Crest / Q000166:cytology*; D009475:Neurons, Afferent / Q000166:cytology; D015398:Signal Transduction; D051899:Smad2 Protein; D013348:Subclavian Artery / Q000002:abnormalities / Q000196:embryology; D015534:Trans-Activators / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053781:Transforming Growth Factor beta2
D015415:Biomarkers; D019002:CD56 Antigen; D004268:DNA-Binding Proteins; C501063:Ncam1 protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2