Smad signaling in the neural crest regulates cardiac outflow tract remodeling through cell autonomous and non-cell autonomous effects.
Neural crest cells (NCCs) are indispensable for the development of the cardiac outflow tract (OFT). Here, we show that mice lacking Smad4 in NCCs have persistent truncus arteriosus (PTA), severe OFT cushion hypoplasia, defective OFT elongation, and mispositioning of the OFT. Cardiac NCCs lacking Smad4 have increased apoptosis, apparently due to decreased Msx1/2 expression. This contributes to the reduction of NCCs in the OFT. Unexpectedly, mutants have MF20-expressing cardiomyocytes in the splanchnic mesoderm within the second heart field (SHF). This may result from abnormal differentiation or defective recruitment of differentiating SHF cells into OFT. Alterations in Bmp4, Sema3C, and PlexinA2 signals in the mutant OFT, SHF, and NCCs, disrupt the communications among different cell populations. Such disruptions can further affect the recruitment of NCCs into the OFT mesenchyme, causing severe OFT cushion hypoplasia and OFT septation failure. Furthermore, these NCCs have drastically reduced levels of Ids and MT1-MMP, affecting the positioning and remodeling of the OFT. Thus, Smad-signaling in cardiac NCCs has cell autonomous effects on their survival and non-cell autonomous effects on coordinating the movement of multiple cell lineages in the positioning and the remodeling of the OFT.
Jia
Qunshan
Q
Renal Division, Department of Internal Medicine, Department of Cell Biology and Physiology, Campus Box 8126, Washington University School of Medicine, St. Louis, MO 63110, USA.
McDill
Bradley W
BW
Li
Song-Zhe
SZ
Deng
Chuxia
C
Chang
Ching-Pin
CP
Chen
Feng
F
D000818:Animals; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D006321:Heart / Q000196:embryology*; D018398:Homeodomain Proteins / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000378:metabolism; D051379:Mice; D032383:Myocytes, Cardiac / Q000166:cytology; D009432:Neural Crest / Q000166:cytology*; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051957:MSX1 Transcription Factor; C084119:MSX2 protein; C484084:Msx1 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse