How to understand estrogen signaling from the phenotypes of ERalpha and ERbeta knockout mice.

Abstract

When ERα knockout mice were created in 1993 (Lubahn et al. 1993), no one was aware of the presence of ERβ and it was assumed that the phenotype of these animals revealed loss of estrogen signaling. We now know that this first ERα knockout was not perfect and that some truncated forms of ERα are expressed in these mice (Couse et al. 1995). We also know that there is another ER, ERβ (Kuiper et al. 1996), so that some estrogen signaling is still intact in ERα -/- mice. Since the development of the original ERα knockout mice, ERβ knockout mice (Krege et al. 1998) and double knockout mice (Ogawa et al. 2000) have been created and intensively examined and the phenotypes often reviewed (Mueller and Korach 2001; Couse et al. 2001; Emmen et al. 2003; Hewitt and Korach 2003). Clearly, disruption of ERa results in severe dysfunction of the ovary, uterus, mammary gland, pituitary and adipose tissue, i.e., the classical estrogen target tissues. At first ERβ was thought to be not very important physiologically because the classical estrogen target tissues of the ERβ -/- mice are much less affected than they are in the ERα -/- mice. It was only when the ERβ -/- mice were examined more carefully that it became apparent that there were many more estrogen target tissues that had been suspected (Nilsson et al. 2001).