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Reporter Expression, Induced by a Growth Hormone Promoter-Driven Cre Recombinase (rGHp-Cre) Transgene, Questions the Developmental Relationship between Somatotropes and Lactotropes in the Adult Mouse Pituitary Gland

Section of Endocrinology, Diabetes, and Metabolism, Department of Medicine (R.M.L., G.A., S.I., R.D.K.) and Transgenic Production Service (R.F.), Research Resources Center, University of Illinois at Chicago, Chicago, Illinois 60612; Research and Development Division (R.M.L., S.I., R.D.K.), Jesse Brown Veteran’s Administration Medical Center, Chicago, Illinois 60612; Sunnybrook and Women’s College Health Sciences Centre (C.L.), Toronto, Ontario, Canada M4N 3M5; and Department of Molecular Pharmacology and Biological Chemistry (H.K.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

Address all correspondence and requests for reprints to: Rhonda D. Kineman, Ph.D., Jesse Brown Veterans Administration Medical Center, Research and Development Division, Mail Post 151, West Side, Suite 6215, 820 South Damen Avenue, Chicago, Illinois 60612. E-mail: Kineman{at}uic.edu.

This report describes the development and validation of the rGHp-Cre transgenic mouse that allows for selective Cre-mediated recombination of loxP-modified alleles in the GH-producing cells of the anterior pituitary. Initial screening of the rGHp-Cre parental line showed Cre mRNA was specifically expressed in the anterior pituitary gland of adult Cre+/– mice and cephalic extracts of e17 Cre+/– fetuses. Heterozygote rGHp-Cre transgenic mice were crossbred with Z/AP reporter mice to generate Cre+/–,Z/AP+/– offspring. In this model system, the GH promoter-driven, Cre-mediated recombination of the Z/AP reporter leads to human placental alkaline phosphatase (hPLAP) expression that serves to mark cells that currently produce GH, in addition to cells that would have differentiated from GH cells but currently do not express the GH gene. Double immunocytochemistry of adult male and female Cre+/–,Z/AP+/– pituitary cells revealed the majority (99%) of GH-producing cells of the anterior pituitary also expressed hPLAP, whereas ACTH-, TSH-, and LH-producing cells were negative for hPLAP, confirming previous reports that corticotropes, thyrotropes, and gonadotropes develop independently of the somatotrope lineage. A small subset (10%) of the prolactin-producing cells was positive for hPLAP, consistent with previous reports showing lactotropes can arise from somatotropes during pituitary development. However, the fact that 90% of prolactin-producing cells were negative for hPLAP suggests that the majority of lactotropes in the adult mouse pituitary gland develop independently of the somatotrope lineage. In addition to developmental studies, the rGHp-Cre transgenic mouse will provide a versatile tool to study the role of a variety of genes in somatotrope function and neoplastic transformation.

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