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Departments of Pathology (T.R.K., M.M.M.), Cell Biology (M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030; Vollum Institute (M.J.L.), L474, Oregon Health Sciences University, Portland, Oregon 97201
Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Baylor College of Medicine, Department of Pathology, One Baylor Plaza, Houston, Texas 77030.
FSH is an 
:ß heterodimeric pituitary glycoprotein that shares a
common -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 FSHß 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 FSHß-deficient
mice by two genetic strategies. In the type I rescue mice, we
introduced into the FSHß-deficient background a 10-kb human FSHß
transgene that is selectively expressed in pituitary gonadotropes. The
presence of this transgene [and thus the interspecies hybrid
(i.e. mouse :human FSHß hormone)] in the
background of mouse FSHß 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 FSHß-deficient female
mice carrying this human FSHß transgene resumed normal
folliculogenesis, were fertile and delivered normal size litters. In
the type II rescue mice, human FSH (human :human FSHß) 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 FSHß-deficient male mice, only
3 out of 10 mouse FSHß-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 FSHß can be corrected by appropriate expression
of human FSH transgenes and that human FSHß gene regulation and
function in the mouse pituitary are indistinguishable from the
endogenous mouse FSHß gene.
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