Differential perturbation of the Fgf/Erk1/2 and Shh pathways in the C57BL/6N and SWV embryonic limb buds after mid-gestational cadmium chloride administration.
The differential susceptibility of inbred mouse strains to teratogen-induced malformations can serve as a model to assess the molecular pathogenesis of dysmorphology. Using such a model, the teratogenic effect of cadmium chloride (CdCl(2)), which results in limb reduction deformities in the C57BL/6N mouse strain, but not in the SWV strain, was found to correlate with reduction of the expression domains of Fgf8/4 (fibroblast growth factor-8 and -4) in the apical ectodermal ridge (AER) and Shh (sonic hedgehog) in the posterior mesenchyme, as well as reduction of MAPK/Erk1/2 (the mitogen-activated protein kinase/extracellular regulated kinase 1/2) phosphorylation (pErk1/2) in the mesenchyme throughout the limb bud. The pattern of pErk1/2 reduction did not consistently reflect the pattern of Fgf8/4 reduction suggesting that CdCl(2) might affect pErk1/2 through an Fgf-independent pathway. Other potential downstream mediators of the Fgf pathway including Mkp3 and Fgf10 as well as pMek (phosphorylated MAPK/Erk1/2 kinase) were not different in limb buds between the two strains at the studied time points. The effect of CdCl(2) on skeletogenesis was traced in time to the early stages of pre-chondrogenic condensation as determined by the Sox9 expression domain. The data of the present study indicate that a differential strain response to CdCl(2)-induced forelimb digital loss may be due to a polymorphic interference with the Fgf/Shh positive feedback loop and Erk1/2 phosphorylation.
Elsaid
Ahmed F
AF
Molecular Toxicology Interdepartmental Program, University of California, Los Angeles School of Public Health, Los Angeles, CA, USA.
Délot
Emmanuèle C
EC
Collins
Michael D
MD
D000818:Animals; D019256:Cadmium Chloride / Q000008:administration & dosage*; D005260:Female; D051519:Fibroblast Growth Factor 4 / Q000378:metabolism*; D051524:Fibroblast Growth Factor 8 / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000378:metabolism*; D018878:Limb Buds / Q000196:embryology*; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D011247:Pregnancy
C496457:Fgf8 protein, mouse; D051519:Fibroblast Growth Factor 4; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D051524:Fibroblast Growth Factor 8; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019256:Cadmium Chloride