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Retinoic acid specifically downregulates Fgf4 and inhibits posterior cell proliferation in the developing mouse
1Department of Human Anatomy and Genetics, University of Oxford, UK.
Abstract:
Retinoic acid, when administered to pregnant mice on d 11.0 of gestation, causes limb skeletal abnormalities consisting of reduced digital number, shortening of the long bones and delayed ossification. We show here that these effects are correlated with a decrease in cell proliferation within 5 h of retinoic acid administration, specifically in the posterior half of the distal limb bud mesenchyme, from which the distal skeletal elements are generated. There is a specific downregulation of Fgf4, a gene known to be involved in limb bud outgrowth and expressed only in the posterior part of the apical ectodermal ridge; Fgf8, which is expressed throughout the apical ectodermal ridge, is unaffected. The reduction in Fgf4 expression is not accompanied by downregulation of Shh, nor of its receptor and downstream target gene Ptc, suggesting that the skeletal reduction defects induced by retinoic acid are mediated specifically by FGF4-induced skeletogenic mesenchymal cell proliferation.
Insights
Retinoic acid causes limb defects by reducing cell proliferation and downregulating Fgf4 in developing mouse limbs. This specific gene downregulation, not affecting Shh, points to FGF4
Area of Science:
- Developmental biology
- Teratology
- Molecular genetics
Background:
- Retinoic acid is a known teratogen causing developmental abnormalities.
- Limb skeletal development is a complex process involving precise gene regulation.
Purpose of the Study:
- To investigate the molecular mechanisms by which retinoic acid induces limb skeletal abnormalities.
- To identify specific genes and cellular processes affected by retinoic acid during limb development.
Main Methods:
- Administration of retinoic acid to pregnant mice at a specific gestational stage (d 11.0).
- Analysis of limb skeletal morphology, including digital number, long bone length, and ossification.
- Assessment of cell proliferation in limb bud mesenchyme.
- Quantitative analysis of gene expression, focusing on Fgf4, Fgf8, Shh, and Ptc.
Main Results:
- Retinoic acid exposure resulted in reduced digital number, shortened long bones, and delayed ossification.
- A significant decrease in cell proliferation was observed in the posterior distal limb bud mesenchyme within 5 hours of retinoic acid administration.
- Specific downregulation of Fgf4 gene expression was detected, while Fgf8 expression remained unaffected.
- Downregulation of Fgf4 was not associated with changes in Shh or Ptc expression.
Conclusions:
- Retinoic acid-induced limb skeletal defects are correlated with decreased cell proliferation in the posterior limb bud.
- The teratogenic effects appear to be mediated specifically through the downregulation of Fgf4, impacting skeletogenic mesenchymal cell proliferation.
- These findings highlight the critical role of FGF4 signaling in normal limb development and retinoic acid-induced teratogenesis.
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