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Two Distinct Mechanisms Elicit Androgen-Dependent Expression of the Mouse Sex-Limited Protein Gene

Department of Human Genetics University of Michigan Medical School Ann Arbor, Michigan 48109-0618

The mouse sex-limited protein (Slp) gene is expressed in liver and kidney of adult males and is testosterone-inducible in females, indicative of androgen dependence. Analysis of mRNA levels and chromatin configuration reveals that this androgen regulation is achieved by distinct means in the two tissues. In the liver, Slp expression requires pituitary function, and specifically, as shown by others, a pulsatile pattern of GH secretion that is itself determined by androgen. After hypophysectomy, Slp synthesis cannot be reestablished in liver by testosterone, although mRNA decline can be slowed. In contrast, in the kidney Slp mRNA is directly induced by androgen in hypophysectomized mice. In vivo footprinting was used to examine the role of the Slp enhancer, which directs androgen-specific transcription in transfection and contains a factor-binding site, FPIV, whose protection in vivo has been correlated with Slp expression. In kidney, FPIV was protected in intact males and hypophysectomized mice supplemented with testosterone, but not in females or untreated hypophysectomized mice, corroborating FPIV’s association with androgen-driven transcription. Surprisingly, protection of FPIV also occurred in liver of hypophysectomized males treated with testosterone, despite the lack of Slp expression. Thus androgen directly affects the Slp enhancer in kidney, where steroid is sufficient for gene activation, as well as in liver, where chromatin remodeling occurs in response to androgen, although GH is clearly required for expression. This may indicate that both GH and androgen signal transduction pathways target the Slp enhancer to elicit precise gene regulation.

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