Experiments designed to examine the role of the first intron in regulation of the Col1a1 gene by transfection and in transgenic mice have led to conflicting conclusions. Recently, Hormuzdi et al. [Hormuzdi, S.G., Penttinen, R., Jaenisch, R., Bornstein, P., 1998. A gene-targeting approach identifies a function for the first intron in expression of the a1(I) collagen. Mol. Cell. Biol. 18, 3368-3375.] created a targeted deletion in this intron in mice and demonstrated an age-dependent reduction in expression of the mutated allele in lung and skeletal muscle. In this study, intratracheal instillation of bleomycin in mice was used to induce pulmonary fibrosis in control and intron-deleted animals. This stimulus for collagen synthesis was associated with a marked upregulation of the intron-deleted allele in mutant mice. Our results establish that the inhibition of expression of the mutant Col1a1 gene is not fixed, since the gene can still respond to physiological signals. We propose that cis-acting elements, elsewhere in the gene, can compensate for the lack of intronic sequences in the mutated Col1a1 allele and account for the conditional nature of the inhibition. This model has the potential to resolve the conflicting results of previous transfection and transgenic experiments in which different fragments of the Col1a1 gene were used.