Irreversible effects of retinoic acid pulse on Xenopus jaw morphogenesis: new insight into cranial neural crest specification

Birth Defects Res B Dev Reprod Toxicol. 2010 Dec;89(6):493-503. doi: 10.1002/bdrb.20269.


Jaws are formed by cephalic neural crest (CNCCs) and mesodermal cells migrating to the first pharyngeal arch (PA1). A complex signaling network involving different PA1 components then establishes the jaw morphogenetic program. To gather insight on this developmental process, in this study, we analyze the teratogenic effects of brief (1-15 min) pulses of low doses of retinoic acid (RA: 0.25-2 µM) or RA agonists administered to early Xenopus laevis (X.l.) embryos. We show that these brief pulses of RA cause permanent craniofacial defects specifically when treatments are performed during a 6-hr window (developmental stages NF15-NF23) that covers the period of CNCCs maintenance, migration, and specification. Earlier or later treatments have no effect. Similar treatments performed at slightly different developmental stages within this temporal window give rise to different spectra of malformations. The RA-dependent teratogenic effects observed in Xenopus can be partially rescued by folinic acid. We provide evidence suggesting that in Xenopus, as in the mouse, RA causes craniofacial malformations by perturbing signaling to CNCCs. Differently from the mouse, where RA affects CNCCs only at the end of their migration, in Xenopus, RA has an effect on CNCCs during all the period ranging from their exit from the neural tube until their arrival in the PA1. Our findings provide a conceptual framework to understand the origin of individual facial features and the evolution of different craniofacial morphotypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Drug-Induced
  • Animals
  • Benzoates / toxicity
  • Drug Antagonism
  • Embryo, Nonmammalian / drug effects*
  • Female
  • Gene Expression Regulation, Developmental / drug effects
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • In Situ Hybridization
  • Jaw / embryology*
  • Jaw Abnormalities / chemically induced
  • Jaw Abnormalities / genetics
  • Jaw Abnormalities / pathology
  • Keratolytic Agents / administration & dosage
  • Keratolytic Agents / toxicity*
  • Leucovorin / pharmacology
  • Morphogenesis / drug effects*
  • Neural Crest / abnormalities
  • Neural Crest / drug effects
  • Neural Crest / embryology*
  • Pulse Therapy, Drug
  • Retinoids / toxicity
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tretinoin / administration & dosage
  • Tretinoin / toxicity*
  • Vitamin B Complex / pharmacology
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis / embryology*


  • Benzoates
  • Dlx5 protein, Xenopus
  • Dlx6 protein, Xenopus
  • Homeodomain Proteins
  • Keratolytic Agents
  • Retinoids
  • Transcription Factors
  • Xenopus Proteins
  • Vitamin B Complex
  • Tretinoin
  • 4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid
  • Leucovorin