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Departments of Human Genetics and Pathology, University of Michigan Medical School Ann Arbor, Michigan 48109-0618
Division of Medical Oncology, University of Colorado Health Sciences Center Denver, Colorado 80262
Animal Reproduction and Biotechnology Laboratory, Department of Physiology, Colorado State University Fort Collins, Colorado 80523
Department of Pharmacology, Case Western Reserve University School of Medicine Cleveland, Ohio 44106
Address requests for reprints to: Dr. Sally A. Camper, Department of Human Genetics, University of Michigan Medical School, Medical Sciences Building II M4708, Ann Arbor, Michigan 48109-0618.
Abstract
LH, FSH, and TSH are heterodimeric glycoprotein hormones composed of a common 
-subunit and unique β-subunits. The -subunit is produced in two distinct specialized cell types of the pituitary gland: gonadotropes, which synthesize LH and FSH, and thyrotropes, which synthesize TSH. We have demonstrated that 313 base pairs of the bovine- subunit promoter direct expression of diphtheria toxin A chain specifically to the gonadotropes in transgenic mice. Animals carrying this transgene generally exhibit reproductive failure and lack of gonadal differentiation, consistent with gonadotrope ablation. Lack of gonadotrope activity was verified by RIA and immunohistochemical staining for LH. The phenotype of these transgenic mice is nearly identical to mice homozygous for the spontaneous mutation, hpg, which is due to a deletion in the gene encoding GnRH. Thyrotrope function was judged normal based on overall growth of the animals, appearance of their thyroids, T4 levels measured by RIA, and immunohistochemical staining for TSH. The ablation of gonadotropes but not thyrotropes suggests that separate cis-acting elements are necessary for expression of the -subunit gene in these two cell types. Pituitary content of ACTH and GH was apparently normal, while PRL synthesis and storage were reduced. Thus, in a pituitary almost completely devoid of gonadotropes, most other pituitary functions were normal. This suggests that most pituitary cells are able to differentiate independently of terminal gonadotrope differentiation and can function in the absence of paracrine signaling provided by gonadotropes.
FOOTNOTES
This work was supported by Basil O'Connor March of Dimes Starter Scholar Award 5–718 (to S.A.C.), Michigan Memorial Phoenix Project Award 5550 (to S.A.C.), a grant from the University of Michigan Horace H. Rackham School of Graduate Studies (to S.A.C.), American Cancer Society Grant CD-62872 (to S.A.C.), National Science Foundation Grant DCB-9004449 (to S.A.C.), Cellular and Molecular Biology Training Grant PHS T32-GM07315 (to S.K.K.), and NIH Grants CA-37238 and CA-42951 (to R.V.L.) and DK-28559 (to J.H.N.).
Received for publication August 5, 1991. Revision received September 16, 1991. Accepted for publication September 16, 1991.
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