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Dramatic Pituitary Hyperplasia in Transgenic Mice Expressing a Human Growth Hormone-Releasing Factor Gene

Kelly E. Mayo, Robert E. Hammer^*, Larry W. Swansont, Ralph L. Brinster, Michael G. Rosenfeld and Ronald M. Evans

Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University Evanston, Illinois 60208
Howard Hughes Medical Institute, University of Texas Southwest Medical School Dallas, Texas 75135
Neuronal Systems Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies San Diego, California 92138
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies San Diego, California 92138
School of Veterinary Medicine, University of Pennsylvania Philadelphia, Pennsylvania 19104
Eukaryotic Regulatory Biology Program, Howard Hughes Medical Institute, School of Medicine, University of California San Diego, California 92037

Address requests for reprints to: Dr. Kelly E. Mayo, Department of Biochemistry, Molecular Biology and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, Illinois 60208.

Abstract

A transgenic animal model system was used to analyze the mitogenic effects of GRF on its target cell, the pituitary somatotroph. We have previously established a strain of mice that express a mouse metallothionein-l/human GRF (hGRF) fusion gene, and that grow to be abnormally large due to GH hypersecretion. We show here that chronic GRF production in these mice leads to the development of enormous pituitary glands. The increase in pituitary size appears to be largely the result of a selective proliferation (hyperplasia) of somatotrophs, the GH-producing cells. This observation provides direct evidence that a neuropeptide may act as a specific trophic factor for its target cell. In addition to this effect on pituitary development, we find that the pituitary is a major site of expression of mouse metallothionein-l/hGRF mRNA, and of hGRF peptide. This tissue specificity was unexpected in that neither component of the fusion gene is highly expressed in the normal pituitary. It suggests that pituitary somatotrophs might produce and respond to GRF in an essentially autocrine fashion in these transgenic animals.

FOOTNOTES

This work was supported by grants from the NIH (to R.L.B. and R.M.E.), and from the Human Growth Foundation (to K.E.M.).

^* Assistant investigator of the Howard Hughes Medical Institute.

Investigators of the Howard Hughes Medical Institute.

Received for publication February 4, 1988. Accepted for publication March 17, 1988.

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