Tissue-specific targeting of the Pthrp gene: The generation of mice with floxed alleles

PTH-related peptide (PTHrP) has been implicated in a variety of development al and homeostatic processes. Although mice homozygous for the targeted dis ruption of the Pthrp gene have greatly expanded our capacity to investigate the developmental roles of the protein, the perinatal lethality of these a nimals has severely hindered the analysis of Pthrp's postnatal physiologica l effects. To overcome this obstacle, we have generated mice homozygous for a floxed Pthrp allele, i.e. two loxP sites flanking exon 4 of the Pthrp ge ne, which encodes most of the protein, with the aim of accomplishing cell t ype-and tissue-specific deletion of the gene. The ability of the Cre enzyme to cause recombination between the loxP sites and excision of the interven ing DNA sequence was tested in vivo by crossing this strain to mice carryin g a cre transgene under the transcriptional control of the human p-actin pr omoter. The ubiquitous deletion of the flexed allele in the cre/loxP progen y resulted in perinatal lethality as a consequence of aberrant endochondral bone formation, fully recapitulating all the phenotypic abnormalities obse rved in the conventional Pthrp knockout mouse. The availability of the flex ed Pthrp mice will serve as a valuable tool in genetic experiments that aim to investigate the physiological actions of Pthrp in the postnatal state.