Cardiac neural crest of the mouse embryo: axial level of origin,migratory pathway and cell autonomy of thesplotch(Sp2H) mutant effect

Abstract

A sub-population of the neural crest is known to play a crucial role in development of the cardiac outflow tract. Studies in avians have mapped the complete migratory pathways taken by `cardiac' neural crest cells en route from the neural tube to the developing heart. A cardiac neural crest lineage is also known to exist in mammals, although detailed information on its axial level of origin and migratory pattern are lacking. We used focal cell labelling and orthotopic grafting, followed by whole embryo culture, to determine the spatio-temporal migratory pattern of cardiac neural crest in mouse embryos. Axial levels between the post-otic hindbrain and somite 4 contributed neural crest cells to the heart, with the neural tube opposite somite 2 being the most prolific source. Emigration of cardiac neural crest from the neural tube began at the 7-somite stage, with cells migrating in pathways dorsolateral to the somite, medial to the somite, and between somites. Subsequently, cardiac neural crest cells migrated through the peri-aortic mesenchyme, lateral to the pharynx, through pharyngeal arches 3, 4 and 6, and into the aortic sac. Colonisation of the outflow tract mesenchyme was detected at the 32-somite stage. Embryos homozygous for the Sp2H mutation show delayed onset of cardiac neural crest emigration, although the pathways of subsequent migration resembled wild type. The number of neural crest cells along the cardiac migratory pathway was significantly reduced in Sp2H/Sp2H embryos. To resolve current controversy over the cell autonomy of the splotchcardiac neural crest defect, we performed reciprocal grafts of premigratory neural crest between wild type and splotch embryos. Sp2H/Sp2H cells migrated normally in the +/+environment, and +/+ cells migrated normally in the Sp2H/Sp2H environment. In contrast, retarded migration along the cardiac route occurred when either Sp2H/+ or Sp2H/Sp2H neural crest cells were grafted into the Sp2H/Sp2Henvironment. We conclude that the retardation of cardiac neural crest migration in splotch mutant embryos requires the genetic defect in both neural crest cells and their migratory environment.

Pax genes: regulators of lineage specification and progenitor cell maintenance

“…Pigmentary abnormalities of the hair, skin and eyes; congenital sensorineural hearing loss; dystopia canthorum; lateral displacement of the ocular inner canthi and upper limb abnormalities Hoth et al, 1993;Zlotogora, 1995;Tekin et al, 2001;Wollnik et al, 2003 'Splotch'/mouse A-to-T transversion of the AG splice acceptor of intron 3 of Pax3 uncertainty about Pax3 requirement for NC migration (Li et al, 1999;Conway et al, 2000;Kwang et al, 2002;Chan et al, 2004) has been addressed recently by looking at the role of Pax3 in migratory cardiac NC cells using the Pax3 mutant Splotch mouse models, all six of which have different mutations in Pax3 (Table 2). In all Splotch mice, cardiac NC cells fail to undergo proliferative expansion prior to migration due to defects intrinsic to the NC cell.…”

Tbx1 controls cardiac neural crest cell migration during arch artery development by regulatingGbx2expression in the pharyngeal ectoderm

“…We speculate that this tight spatiotemporal control of gene expression is required for correct patterning of cNCCs. Indeed, cNCCs emigrate from the neural tube at the 7-9 somites stage in the mouse embryo (Chan et al, 2004;Trainor, 2005). Therefore, the timing of Tbx1, Gbx2 and Slit2 expression, accompanied by the position of the PSE, immediately juxtaposed to cNCCs as they start to migrate, is likely to be instructive.…”

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

“…NC cells that migrate into the pharyngeal arches 3-6 and into the heart are called cardiac NC cells. The cardiac NC originates from the region of the dorsal neural tube located between the otic pit and the 4th somite (Chan et al, 2004;Hutson and Kirby, 2007).…”