A signaling cascade involving endothelin-1, dHAND and Msx1 regulates development of neural-crest-derived branchial arch mesenchyme

Abstract

Numerous human syndromes are the result of abnormal cranial neural crest development. One group of such defects, referred to as CATCH-22 (cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, associated with chromosome 22 microdeletion) syndrome, exhibit craniofacial and cardiac defects resulting from abnormal development of the third and fourth neural crest-derived branchial arches and branchial arch arteries. Mice harboring a null mutation of the endothelin-1 gene (Edn1), which is expressed in the epithelial layer of the branchial arches and encodes for the endothelin-1 (ET-1) signaling peptide, have a phenotype similar to CATCH-22 syndrome with aortic arch defects and craniofacial abnormalities. Here we show that the basic helix-loop-helix transcription factor, dHAND, is expressed in the mesenchyme underlying the branchial arch epithelium. Further, dHAND and the related gene, eHAND, are downregulated in the branchial and aortic arches of Edn1-null embryos. In mice homozygous null for the dHAND gene, the first and second arches are hypoplastic secondary to programmed cell death and the third and fourth arches fail to form. Molecular analysis revealed that most markers of the neural-crest-derived components of the branchial arch are expressed in dHAND-null embryos, suggesting normal migration of neural crest cells. However, expression of the homeobox gene, Msx1, was undetectable in the mesenchyme of dHAND-null branchial arches but unaffected in the limb bud, consistent with the separable regulatory elements of Msx1 previously described. Together, these data suggest a model in which epithelial secretion of ET-1 stimulates mesenchymal expression of dHAND, which regulates Msx1 expression in the growing, distal branchial arch. Complete disruption of this molecular pathway results in growth failure of the branchial arches from apoptosis, while partial disruption leads to defects of branchial arch derivatives, similar to those seen in CATCH-22 syndrome.

History of the study of the neural crest (review)

“…По мере того как вентролатеральный поток проходит через передние половины сомитов, некоторые клетки остаются там и дифференцируются в дорсальные корешковые ганглии, в то время как другие дают начало симпатическим ганглиям [99], шванновским и адреномедуллярным клеткам [100,101]. Сердечный нервный гребень простирается от первого до третьего сомита и участвует в формировании сердечной перегородки, электрогенерирующей и проводящей системы сердца [102][103][104].…”

Cartilage Diversification and Modularity Presaged the Evolution of the Gnathostome Head Skeleton

“…The vertebrate jaw is characterized by dorso-ventral patterning in the rst pharyngeal arch via nested dlx expression and jagged-edn-bmp signaling (Talbot et al, 2010;Walker et al, 2006), producing an intermediate domain that expresses a suite of genes like gdf5 and nkx3.2 where the future jaw joint (Miller et al, 2003;Thomas et al, 1998). It has been shown that the transcription factor barx1 is involved with positioning this future jaw joint, as its expression is anti-correlated with this tissue, and its knockdown results in ectopic joint tissue in zebra sh (Nichols et al, 2013;Sperber & Dawid, 2008;Square et al, 2015).…”