Retinoic acid down-regulates Tbx1 expression and induces abnormal differentiation of tongue muscles in fetal mice

Dev Dyn. 2008 Oct;237(10):3059-70. doi: 10.1002/dvdy.21715.


Excess retinoic acid (RA) during pregnancy can cause various developmental anomalies in both humans and rodents. We investigated the mechanisms underlying the aberrant differentiation of tongue muscles in fetal mice exposed to exogenous RA in utero. RA-degrading enzymes (Cyp26a1 and Cyp26b1) were expressed at early stages of normal tongue development, but exogenous RA perturbed their expression in the fetal tongue. RA is normally distributed in the developing tongue muscles but its localization was disrupted by exogenous RA. After RA treatment, myogenic determination factors were reduced and the differentiation was significantly suppressed in tongue muscles. Tbx1, a candidate gene of DiGeorge syndrome, was down-regulated in the fetal tongue in response to excess RA. Moreover, Tbx1 as well as myogenic determination factors were not observed in tongue muscle primordia of Cyp26b1-/- fetuses. Our study suggests that RA signaling may play an essential role in tongue muscle differentiation via the regulation of Tbx1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cytochrome P-450 Enzyme System / deficiency
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Down-Regulation / drug effects
  • Gene Expression Regulation, Developmental
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Scanning
  • Muscle Development / drug effects
  • Muscles / cytology
  • Muscles / drug effects
  • Muscles / embryology*
  • Muscles / metabolism*
  • Retinoic Acid 4-Hydroxylase
  • Signal Transduction / drug effects
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism*
  • Tongue / abnormalities*
  • Tongue / cytology
  • Tongue / drug effects
  • Tongue / metabolism*
  • Tretinoin / pharmacology*


  • T-Box Domain Proteins
  • Tbx1 protein, mouse
  • Tretinoin
  • Cytochrome P-450 Enzyme System
  • CYP26B1 protein, human
  • Cyp26a1 protein, mouse
  • Cyp26b1 protein, mouse
  • Retinoic Acid 4-Hydroxylase