Multiple lineage-specific roles of Smad4 during neural crest development

Abstract

During vertebrate development, neural crest cells are exposed to multiple extracellular cues that drive their differentiation into neural and non-neural cell lineages. Insights into the signals potentially involved in neural crest cell fate decisions in vivo have been gained by cell culture experiments that have allowed the identification of instructive growth factors promoting either proliferation of multipotent neural crest cells or acquisition of specific fates. For instance, members of the TGFbeta factor family induce neurogenesis and smooth muscle cell formation at the expense of other fates in culture. In vivo, conditional ablation of various TGFbeta signaling components resulted in malformations of non-neural derivatives of the neural crest, but it is unclear whether these phenotypes involved aberrant fate decisions. Moreover, it remains to be shown whether neuronal determination indeed requires TGFbeta factor activity in vivo. To address these issues, we conditionally deleted Smad4 in the neural crest, thus inactivating all canonical TGFbeta factor signaling. Surprisingly, neural crest cell fates were not affected in these mutants, with the exception of sensory neurogenesis in trigeminal ganglia. Rather, Smad4 regulates survival of smooth muscle and proliferation of autonomic and ENS neuronal progenitor cells. Thus, Smad signaling plays multiple, lineage-specific roles in vivo, many of which are elicited only after neural crest cell fate decision.

Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells

“…Abbreviations: CM, chondrogenesis permissive medium; NC, neural crest; NCSC, neural crest stem cell; p-HH3, phosphorylated histone H3; TGFb, transforming growth factor b. substitute in part for TGFb during further PA development. These findings are in agreement with previous reports that, unlike in defined minimal medium, smooth muscle cells can form from NCSCs in complex medium, even if canonical signaling by TGFb family factors is completely inactivated [30]. Furthermore, although TGFb priming was required for NC cells to generate differentiated osteoblasts, early osteogenic transcription factors were also induced in untreated NC cells incubated in osteogenesis permissive conditions.…”

“…S3D, S3E). Thus, smooth muscle formation and chondrogenesis was impaired but not completely abrogated in Tgfbr2 cko PA cells, pointing to the presence of cues partially substituting for TGFb signaling [30]. In contrast, although control cell cultures readily produced osteoblasts when incubated in OM medium, mutant cells exhibited no signs of osteoblast differentiation even after 18 days of culture (Fig.…”

Ezh2 is required for neural crest-derived cartilage and bone formation

“…Clearly, region-specific Hox gene regulation and the potential to form skeletal structures must involve other factors as well, given that Ezh2 and H3K27me3 are also broadly expressed in more posterior NCCs, which in vivo do not form cartilage and bone. These factors include intrinsic cues that distinguish CNCCs from more caudal NCCs, as suggested, for example, by clonal assays in cell culture or by the in vivo manipulation of signaling pathways regulating neural and osteochondrogenic fates (Büchmann-Møller et al, 2009;Calloni et al, 2009;John et al, 2011). The nature of these cues and their potential functional interaction with epigenetic regulators, including Ezh2, remain to be determined.…”

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].…”