Abstract
Genetically different inbred strains of mice have markedly varying susceptibilities to the production of cleft palate by a standard dosage regimen of corticoids at the critical period of palatal organogenesis. This susceptibility to corticoid-induced cleft palate has recently been shown to be regulated by genes in or near the H-2 locus. In order to determine whether susceptibility to cortisone-induced cleft palate may be mediated by genetic differences in a cytosolic corticoid receptor protein, fetal palatal anlagen were obtained by microdissection of the upper and lower fetal jaws on day 11 of gestation 1 hour after maternal injection of 5 μCi (1, 2, 6, 7- 3H)-cortisol. Cytosols of maternal palates and fetal jaws of five inbred strains and of the congenic strains B10, and B10-A a which has the genetic background of B10, but the H-2a allele of the most sensitive strain, A/J, were prepared. The total level of cytosolic protein binders of 3H-cortisol in maternal and fetal palates on day 11 of gestation correlates with susceptibility to cleft palate and the H-2 genotype. After microelectrofocusing, only one maternal and fetal palatal cytosol binder for 3H-cortisol (pI 6.9-7.0) is found to correlate with susceptibility to cleft palate and the H-2 genotype. Thus, a gene product in or near the H-2 locus appears to be the glucocorticoid receptor whose level must be elevated for a cleft palate to occur. This is the only malformation that has been associated so far with the H-2 locus. This mechanism may be applicable to other teratogens as well.
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