Studies on mammalian growth control: The phenotypic and molecular characterization of the pygmy mouse

Insertional mutagenesis in mouse via microinjection results in the creation of unique developmental mutants as well as providing a means of cloning the disrupted locus. Two insertional mutants, called A and B, arose as autosomal recessive mutations in the same founder transgenic mouse. Mice homozygous for either mutation were called mini-mice because their final body weight is only 40% the size of wildtype littermates. Most tissues of mini-mice are reduced in proportion with the overall reduction in their body weight except for smaller adrenals and a normal sized brain. In addition, mini-mice have much less adipose tissue than wildtype or hemizygous littermates, have normal levels of circulating growth hormone and are subfertile. A developmental analysis detected the initial appearance of the small phenotype at day 15.5 of gestation.;The disrupted locus was cloned and a genetic and molecular analysis determined that the insertional mutants were allelic to a spontaneous mutation that mapped to mouse chromosome 10, called pygmy (pg). Further analysis revealed that in all three mutants, deletions of the pygmy locus had occurred. Over 335 kb of the mouse pygmy locus was characterized by overlapping lambda clones, defining a 56 kb region of common deletion shared among the three mutants. Exons within this 56 kb region were isolated by the exon trapping method and sequence analysis demonstrated 100% homology to the previously isolated non-histone, chromatin associated protein HMGI-C. Northern analysis detects a 4.1 kb transcript in wildtype mouse embryonic RNA which is missing from the A, B, and pg mutants as well as from a 4th pygmy mutant, In (10)17Rk, which has an inversion in mouse chromosome 10.;Northern analysis determined that the highest expression of HMGI-C occurs during embryogenesis, while in situ hybridization of 10.5-16.5 d.p.c. embryos localized this expression to the mesenchymal component of tissues. The study of HMGI-C, both its normal expression and the effect of its disruption in the pygmy mouse model, should illuminate the in vivo role of HMGI-C in mammalian growth and development.