High specificity of Müllerian-inhibiting substance signaling in vivo.

Female transgenic mice that ectopically express high levels of human Müllerian-inhibiting substance (hMIS) under the control of the mouse metallothionein (MT) promoter lack a uterus, oviducts, and ovaries. The loss of the uterus and oviducts is consistent with the known activities for MIS. However, it is not clear if the loss of the ovaries in these transgenic females is caused by interactions of MIS with its normal receptor signaling pathway or by abnormal interactions with other transforming growth factor-beta (TGF-beta) super family receptor signaling pathways. To address this question, female mice carrying the MT-hMIS transgene that were also homozygous for a targeted deletion of the MIS type II receptor gene were generated. Although these females had high levels of circulating hMIS, they had normal reproductive tracts and ovaries with germ cells. In addition, these females were able to become pregnant and gave birth to pups. These findings demonstrate that all of the abnormalities of the reproductive system that are found in female transgenic mice that ectopically express high levels of hMIS are caused by signaling through the MIS type II receptor. These in vivo data demonstrate a high specificity for MIS and its receptor.