Genetic Rescue of Follicle-Stimulating Hormone β-Deficient Mice

• Published in: Endocrinology (Philadelphia) 1998-07, Vol.139 (7), p.3289-3295
• Main Authors: Kumar, T. Rajendra, Low, Malcolm J., Matzuk, Martin M.
• Format: Article
• Language: English
• Subjects: Females; Follicle-stimulating hormone; Folliculogenesis; Gene regulation; Glycoproteins; Luteinizing hormone; Males; Metallothionein; Motility; Mutants; Parturition; Phenotypes; Pituitary; Pituitary (anterior); Pregnancy complications; Sperm; Testes; Transgenes
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.139.7.6111

Abstract FSH is an α:β heterodimeric pituitary glycoprotein that shares a common α-subunit with LH and TSH. To study the role of FSH in mammalian reproduction, we have previously generated an FSH-deficient mouse model using embryonic stem (ES) cell technology by introducing a null mutation in the unique FSHβ gene. Male mice deficient in FSH are fertile despite their small testes and reduced sperm number and motility. In contrast, FSH-deficient female mice are infertile due to a block in folliculogenesis at the preantral stage. In this set of experiments, we have rescued the mutant phenotypes of FSHβ-deficient mice by two genetic strategies. In the type I rescue mice, we introduced into the FSHβ-deficient background a 10-kb human FSHβ transgene that is selectively expressed in pituitary gonadotropes. The presence of this transgene [and thus the interspecies hybrid (i.e. mouse α:human FSHβ hormone)] in the background of mouse FSHβ deficiency completely restored the testis size, sperm number, and motility defects to levels comparable to those seen in control male mice. All of the mouse FSHβ-deficient female mice carrying this human FSHβ transgene resumed normal folliculogenesis, were fertile and delivered normal size litters. In the type II rescue mice, human FSH (human α:human FSHβ) was ectopically produced from multiple tissues in the mutant background using a mouse metallothionein-I promoter. Whereas ectopic production of human FSH completely rescued the mouse FSHβ-deficient male mice, only 3 out of 10 mouse FSHβ-deficient females bearing these human FSH transgenes were fertile and carried their pregnancies to term and parturition. We conclude that the resultant phenotypes due to a genetic deficiency of mouse FSHβ can be corrected by appropriate expression of human FSH transgenes and that human FSHβ gene regulation and function in the mouse pituitary are indistinguishable from the endogenous mouse FSHβ gene.