title: Exogenous retinoic acid induces digit reduction in opossums (Monodelphis domestica) by disrupting cell death and proliferation, and apical ectodermal ridge and zone of polarizing activity function.
abstract: BACKGROUND
  Retinoic acid (RA) is a vitamin A derivative. Exposure to exogenous RA generates congenital limb malformations (CLMs) in species from frogs to humans. These CLMs include but are not limited to oligodactyly and long-bone hypoplasia. The processes by which exogenous RA induces CLMs in mammals have been best studied in mouse, but as of yet remain unresolved.
  
  
  METHODS
  We investigated the impact of exogenous RA on the cellular and molecular development of the limbs of a nonrodent model mammal, the opossum Monodelphis domestica. Opossums exposed to exogenous retinoic acid display CLMs including oligodactly, and results are consistent with opossum development being more susceptible to RA-induced disruptions than mouse development.
  
  
  RESULTS
  Exposure of developing opossums to exogenous RA leads to an increase in cell death in the limb mesenchyme that is most pronounced in the zone of polarizing activity, and a reduction in cell proliferation throughout the limb mesenchyme. Exogenous RA also disrupts the expression of Shh in the zone of polarizing activity, and Fgf8 in the apical ectodermal ridge, and other genes with roles in the regulation of limb development and cell death.
  
  
  CONCLUSIONS
  Results are consistent with RA inducing CLMs in opossum limbs by disrupting the functions of the apical ectodermal ridge and zone of polarizing activity, and driving an increase in cell death and reduction of cell proliferation in the mesenchyme of the developing limb.
authors: School of Integrative Biology, University of Illinois, Urbana, Illinois.
authors: Anna C
authors: AC
authors: Molineaux
authors: Jennifer A
authors: JA
authors: Maier
authors: Teresa
authors: T
authors: Schecker
authors: Karen E
authors: KE
authors: Sears
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004475:Ectoderm / Q000002:abnormalities / Q000196:embryology; D006614:Hindlimb / Q000002:abnormalities / Q000196:embryology; D007641:Keratolytic Agents / Q000009:adverse effects* / Q000494:pharmacology; D009893:Opossums / Q000002:abnormalities / Q000196:embryology; D014212:Tretinoin / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: D007641:Keratolytic Agents; D014212:Tretinoin
keywords: Fgf8; RA; Shh; limb development; teratogen