HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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.
AuthorsT Thomas, H Kurihara, H Yamagishi, Y Kurihara, Y Yazaki, E N Olson, D Srivastava
JournalDevelopment (Cambridge, England) (Development) Vol. 125 Issue 16 Pg. 3005-14 (Aug 1998) ISSN: 0950-1991 [Print] England
PMID9671575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • Endothelin-1
  • Hand1 protein, mouse
  • Hand2 protein, mouse
  • Homeodomain Proteins
  • MSX1 Transcription Factor
  • RNA Probes
  • Transcription Factors
  • Zebrafish Proteins
  • hand2 protein, zebrafish
  • helix-loop-helix protein, eHAND
Topics
  • Animals
  • Apoptosis (physiology)
  • Basic Helix-Loop-Helix Transcription Factors
  • Branchial Region (cytology)
  • DNA-Binding Proteins (genetics, physiology)
  • Down-Regulation (physiology)
  • Endothelin-1 (genetics)
  • Gene Expression Regulation, Developmental (genetics)
  • Genes, Homeobox (genetics)
  • Helix-Loop-Helix Motifs (physiology)
  • Histocytochemistry
  • Homeodomain Proteins (genetics)
  • In Situ Hybridization
  • MSX1 Transcription Factor
  • Mesoderm (physiology)
  • Mice
  • Mice, Knockout
  • Mutation (genetics)
  • RNA Probes (genetics)
  • Signal Transduction (physiology)
  • Transcription Factors (genetics, physiology)
  • Zebrafish Proteins

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: