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

Tiffani Thomas, Hiroki Kurihara, Hiroyuki Yamagishi, Yukiko Kurihara, Yoshio Yazaki, Eric N. Olson, Deepak Srivastava

Research output: Contribution to journalArticle

211 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3005-3014
Number of pages10
JournalDevelopment
Volume125
Issue number16
StatePublished - Aug 1998

Keywords

  • Apoptosis
  • Branchial arch
  • CATCH-22
  • Endothelin
  • Human
  • Mouse
  • Msx1
  • Neural crest
  • dHAND

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Fingerprint Dive into the research topics of 'A signaling cascade involving endothelin-1, dHAND and Msx1 regulates development of neural-crest-derived branchial arch mesenchyme'. Together they form a unique fingerprint.

Cite this