Smad signaling in the neural crest regulates cardiac outflow tract remodeling through cell autonomous and non-cell autonomous effects

Abstract

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.

BMP-mediated inhibition of FGF signaling promotes cardiomyocyte differentiation of anterior heart field progenitors

“…Taken together, these studies suggest that both cardiac neural crest (interacting with SHF progenitors) and cranial neural crest cells (in the AHF niche) buffer proliferative signals (presumably FGFs) secreted from the endoderm and ectoderm in order to promote myocardial and myogenic differentiation, as well as migration into the outflow tract and branchial arches, respectively. Other examples of non-cell autonomous roles of cardiac/cranial neural crest in the regulation of the AHF niche were demonstrated in mice lacking either Smad4 (Jia et al, 2007) or the BMP receptor Alk2 (Kaartinen et al, 2004) in neural crest cells. Both of these mouse models revealed abnormal differentiation of AHF/SHF progenitors and severe OFT defects.…”

BMP signaling regulates sympathetic nervous system development through Smad4-dependent and -independent pathways

“…Deletion of Smad4 in the NC lineage using Wnt1-Cre (Jia et al, 2007;Ko et al, 2007;Nie et al, 2008) showed that Smad4 cKO embryos died at 12 dpc, with pooling of blood in the periphery that resembled defects in SNS development (Lim et al, 2000;Morikawa and Cserjesi, 2008;Morikawa et al, 2007), suggesting Smad4 plays a role in SNS development. To determine the role of the canonical BMP pathway in SNS development, we deleted Smad4 and simultaneously marked the NC lineage to examine how its loss affected early SNS development (Fig.…”

Stage- and area-specific control of stem cells in the developing nervous system

“…Wnt signaling on its own instructively promotes sensory neurogenesis in eNCSCs [19,20]. BMP signaling alone, on the other hand, instructively drives eNCSCs into the autonomic lineage in vitro [21], while in vivo BMP signaling regulates proliferation, differentiation and survival of NC-derived cells in a lineage specific fashion [22][23][24]. Cells with NCSC-like features can also be found in various postmigratory target structures of the neural crest, like in the embryonic sciatic nerve [25], adult skin [26,27], gut [28], adult dorsal root ganglia (DRG), whisker pad, and bone marrow [29].…”