Analysis of receptor mechanisms involved in the hemopoietic effects of androgens: use of the Tfm mutant.

The insensitivity of Tfm mutant mice to androgens is due to a greatly diminished ability to bind 5alpha-dihydrotestosterone to androgen-binding receptors in the cytoplasm of target tissues. Testosterone stimulates hemopoiesis through several mechanisms. The Tfm mutant mouse was used in an attempt to delineate hemopoietic effects of androgens that are mediated by androgen-binding receptors from those that require other cellular mechanisms. Mice of the Tfm mutant and related (androgen-binding) genotypes were treated with multiple doses of 5alpha-dihydrotestosterone (5alpha-DHT). The Tfm mutant was not stimulated to incorporate 59Fe, suggesting that androgen-binding receptors mediate this hemopoietic action of 5alpha-DHT. In contrast, the mutation did not block the ability of a single dose of 5alpha-DHT to increase the absolute number of committed granulocyte/macrophage precursors (CFU-C) in the femurs of mutant mice. The latter finding suggests that androgen-binding receptors are not involved in the mechanisms that lead to amplification of the CFU-C population by 5alpha-DHT. Tfm mutant mice respond to nonandrogenic stimuli of erythropoiesis. These findings emphasize the specificity of the diminished ability of the Tfm mutant mouse to respond erythropoietically to androgen. Accordingly, the Tfm mutant mouse appears to be a useful analytical tool for studying mechanisms underlying the hematopoietic effects of testosterone and related steroids.