Woloschak, Gayle E.

Abstract Mice bearing the autosomal recessive gene "wasted" (wst/wst) have been reported to develop low or absent secretory immune responses, abnormal DNA repair mechanisms, and uncoordinated body movements. We have performed a detailed immunologic and neuropathologic investigation of the disease. Con A and LPS mitogenic responses of splenic lymphocytes as well as total serum Ig levels were equivalent in wst/wst and undiseased control littermates (wst/+ and +/+). Amounts of serum IgM, IgG2a, IgG2b, IgG3, and IgA, however, were reduced in wst/wst animals. FACS analyses of Ig+ and isotype-specific B cell populations revealed similar percentages of Ig+, mu +, gamma +, and alpha + cells in wst/wst and control mice. However, the percentage of "very bright" Ig+ cells as well as "very bright" heavy and light chain-specific B cell subpopulations was increased at least 10-fold in wst/wst B cells as compared with littermate controls. In addition, studies of Ig-specific mRNA accumulation in these animals revealed significant decreases in all isotypes except gamma 3 in spleens of wst/wst mice as compared with littermate controls. Neuropathologic studies in wst/wst mice showed prominent vacuolar degeneration of neurons within anterior horns of the spinal cord and the motor nuclei of the brain stem. No abnormalities were noted in Purkinje cells of the cerebellum nor within myelin sheaths. The abnormalities in the nervous system resembled human motor neuron disease rather than ataxia-telangiectasia as had been reported previously. The immunologic studies suggest that splenic B cells from wst/wst mice have a defect in the ability to "switch" from membrane to secreted Ig. In addition, this mutation provides a mechanism to study regulatory interactions between the immune and nervous systems.

The mRNA levels of genes known to be regulated by sex steroids are not altered until 1 hr or longer after steroid treatment, although the steroid receptor complexes are bound to nuclear acceptor sites within 5 min. In a search for early regulation of gene transcription, total chick oviduct RNA was isolated at various times after injection (i.p.) of progesterone and analyzed for c-myc expression. Levels of c-myc mRNA began to decrease in response to progesterone by 10 min after injection. The mRNA levels continued to decrease, reached a 70% reduction at 30 min, and returned to control values by 8 hr after steroid injection. Changes in alpha-tubulin mRNA levels were markedly less in these same RNA preparations. The effect was dependent on the dose of the steroid and was target-tissue specific. These changes occurred much more rapidly than changes in egg-white protein mRNA levels. Vehicle alone did not alter c-myc mRNA levels. Early regulated genes such as c-myc may represent the initial site of action of steroid receptors in the genome.