Parental origin-specific developmental defects in mice with uniparental disomy for chromosome 12

Genetic analysis has shown that the distal portion of mouse chromosome 12 i s imprinted; however, the developmental roles of imprinted genes in this re gion are not known. We have therefore generated conceptuses with uniparenta l disomy for chromosome 12, in which both copies of chromosome 12 are eithe r paternally or maternally derived (pUPD12 and mUPD12, respectively). Both types of UPD12 result in embryos that are non-viable and that exhibit disti nct developmental abnormalities. Embryos with pUPD12 die late in gestation, whereas embryos with mUPD12 can survive to term but die perinatally, The m UPD12 conceptuses are invariably growth-retarded while pUPD12 conceptuses e xhibit placentomegaly. Skeletal muscle maturation defects are evident in bo th types of UPD12 In addition, embryos with paternal UPD12 have costal cart ilage defects and hypo-ossification of mesoderm-derived bones. In embryos w ith mUPD12, the development of the neural crest-derived middle ear ossicles is defective. Some of these anomalies are consistent with those seen with uniparental disomies of the orthologous chromosome 14 region in humans. Thu s, imprinted genes on chromosome 12 are essential for viability, the regula tion of prenatal growth, and the development of mesodermal and neural crest -derived lineages.