Altered localization of gene expression in both ectoderm and mesoderm is associated with a murine strain difference in retinoic acid-induced forelimb ectrodactyly

作者：Shimizu Hirohito; Lee Grace S; Beedanagari Sudheer R; Collins Michael D^*

来源：Birth Defects Research Part A: Clinical and Molecular Teratology , 2007, 79(6): 465-482.

DOI：10.1002/bdra.20358

• postaxial ectrodactyly
• retinoic acid
• mouse strain
• apical ectodermal ridge (AER)
• zone of polarizing activity (ZPA)
• gene expression pattern

BACKGROUND: Defects in digit number or fusion as a teratogenic response are well documented in humans and intensively studied in various mouse models. Maternal exposure to excess levels of all-trans-retinoic acid (RA) at gestational day 9.5 induces postaxial ectrodactyly (digit loss) in the murine C57BL/6N strain but not in the SWV/Fnn strain. METHODS: Whole-mount in situ hybridization was used to examine the differential expression of limb patterning genes at the transcriptional level between the two mouse strains following the maternal exposure to a teratogenic level of RA. The detection of a gene with altered expression was followed by either the evaluation of other genes that were synexpressed or with an assessment of downstream genes. RESULTS: In the C57BL/6N limb bud following maternal RA administration, gene-specific perturbations were observed within hours of the RA injection in the posterior pre-AER (apical ectodermal ridge) (Fgf8, Dlx3, Bmp4, Sp8, but not Dlx2 or p63), whereas these genes were normally expressed in the SWV/Fnn limb bud. Furthermore, although RA caused comparable reductions of Shh expression between the strains in the 12 h after administration, some Shh downstream genes were differentially expressed (e.g., Gli1, Ptc, and Hoxd13), whereas others were not (e.g., Fgf4, Bmp4, and Gremlin). CONCLUSIONS: It is proposed that altered gene expression in both pre-AER and mesoderm is involved in the pathogenesis of postaxial digit loss, and that because the alterations in the pre-AER occur relatively early in the temporal sequence of events, those changes are candidates for an initiating factor in the malformation.

• 出版日期2007-6