Signals controlling neural crest contributions to the heart

Abstract

Cardiac neural crest cells represent a unique subpopulation of cranial neural crest cells that are specified, delaminate and migrate from the developing neural tube to the caudal pharynx where they support aortic arch artery development. From the caudal pharynx, a subset of these cells migrates into the cardiac outflow tract where they are needed for outflow septation. Many signaling factors are known to be involved in specifying and triggering the migration of neural crest cells. These factors have not been specifically studied in cardiac crest but are assumed to be the same as for the other regions of crest. Signaling factors like Ephs and Semaphorins guide the cells into the caudal pharynx. Support of the cells in the pharynx is from endothelin, PDGF and the TGFbeta/BMP signaling pathways. Mutants in the TGFbeta/BMP pathway show abnormal migration or survival in the pharynx, whereas the migration of the neural crest cells into the outflow tract is orchestrated by Semaphorin/Plexin signaling. Although TGFbeta family members have been well studied and show defective neural crest function in outflow septation, their mechanism of action remains unclear.

Keywords: cardiac neural crest; cardiovascular development; signaling.

Figure 1

Composite representation of a transverse section of a chick embryo. Neural crest, represented in yellow, emigrate from the dorsal neural tube. (1) Signals involved in specification and delamination of neural crest (blue triangles) are represented at stages 10–12 in the developing chick embryo although specification likely occurs much earlier, and it is clear that Wnt, Bmp, Fgf and RA are involved in these developmental processes. (2) Cardiac neural crest migrate into pharyngeal arches 3, 4, and 6 from stages 13–18 (blue squares). Eph/Ephrins are important signaling cues, and it is likely that Fgf is also involved. (3) Endothelin and PDGF signaling supports the survival and maintenance of the neural crest in the pharyngeal region from stages 18–22. (4) While it remains unclear exactly how neural crest forms the outflow septation complex from stages 26–34 (blue pentagons), Semaphorin signaling is involved in this process. TGF/BMP signaling is also involved in this process, but its specific role is unresolved.

Figure 2

The critical developmental steps in cardiac neural crest migration occur in the same order and are conserved between chick and mouse. Delamination from the neural tube, the population of the pharyngeal arches, and septation of the cardiac outflow tract occur similarly across species with divided systemic and pulmonary circulations.

Figure 3

Components of TGFβ superfamily signaling many of which have been evaluated by conditional deletion in the neural crest. TGFβ ligands typically activate Smads 2/3 or 1/5, whereas BMP ligands activate Smads 1/5/8. Smads 1,2,3,4 and 8 are also known as receptor-regulated or R-Smads. Smad 4 is a co-Smad and is activated via both types of ligands. Upon activation, the Smad4 complex is translocated to the nucleus where it drives transcription of target genes. The Smads can interact with multiple transcriptional regulators, one of which is Lef/TCF.