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H Aslam
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G Rosiepen
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H Krishnamurthy
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M Arslan
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G Clemen
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E Nieschlag
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GF Weinbauer
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Although the gonadotropic control of the spermatogenic process is well established, the endocrine regulation of the timing and kinetics of germ cell development has received little attention. We found previously that the administration of a GnRH antagonist (ANT) over a period of 25 days could retard spermatid development and slightly prolong cycle length in intact adult cynomolgus monkeys (Macaca fascicularis). The aim of the present study was to investigate the effects of extended exposure to ANT on the duration of the cycle of the seminiferous epithelium in the monkey. Additionally, the duration of spermatogenesis was studied in the ANT-exposed rat model. In experiment 1, monkeys were given either saline or ANT (n=6/group) and on day 30 all animals received a single injection of 5-bromodeoxyuridine (BrdU) to label S-phase germ cells. Testicular biopsies were taken on days 39, 43, 47 and 51 (end of treatment) for BrdU localization and flow cytometric analysis. ANT treatment suppressed hormone levels, reduced testis size by >70% and severely impaired germ cell production. Despite these alterations, cycle duration remained unchanged at all time-points compared with controls (10.12+/-0.15 days vs 10.16+/- 0.44 days). In experiment 2, adult male Sprague-Dawley rats (n=15/group) received either vehicle (VEH) or ANT for 14 days and received BrdU injection on day 2. Cycle duration was found to be shorter in the ANT-treated group (12.45+/-0.09 days) than in the control group (12.75+/-0.08, P<0.05). As spermatogenic cycle length in this control group was longer than that of our historical controls (range: 12.37-12.53 days), experiment 2 was repeated (n=10/group). In experiment 3, cycle duration was 12.51+/-0.02 for VEH and 12.46+/-0.05 for the ANT-treated group (P>0.05) in both species. We concluded that the duration of the cycle of the seminiferous epithelium in monkeys and rats is independent of gonadotropins but is rather regulated by the spermatogenic tissue itself.

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Victoria E DeMambro
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Masanobu Kawai The Jackson Laboratory, Medical Center Research Institute, John Hopkins University, Massachusetts General Hospital, Department of Research, 600 Main Street, Bar Harbor, Maine 04609, USA

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Thomas L Clemens The Jackson Laboratory, Medical Center Research Institute, John Hopkins University, Massachusetts General Hospital, Department of Research, 600 Main Street, Bar Harbor, Maine 04609, USA

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Keertik Fulzele The Jackson Laboratory, Medical Center Research Institute, John Hopkins University, Massachusetts General Hospital, Department of Research, 600 Main Street, Bar Harbor, Maine 04609, USA

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Jane A Maynard
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Caralina Marín de Evsikova
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Kenneth R Johnson
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Ernesto Canalis The Jackson Laboratory, Medical Center Research Institute, John Hopkins University, Massachusetts General Hospital, Department of Research, 600 Main Street, Bar Harbor, Maine 04609, USA

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Wesley G Beamer
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Clifford J Rosen The Jackson Laboratory, Medical Center Research Institute, John Hopkins University, Massachusetts General Hospital, Department of Research, 600 Main Street, Bar Harbor, Maine 04609, USA

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Leah Rae Donahue
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A spontaneous mouse mutant, designated ‘small’ (sml), was recognized by reduced body size suggesting a defect in the IGF1/GH axis. The mutation was mapped to the chromosome 1 region containing Irs1, a viable candidate gene whose sequence revealed a single nucleotide deletion resulting in a premature stop codon. Despite normal mRNA levels in mutant and control littermate livers, western blot analysis revealed no detectable protein in mutant liver lysates. When compared with the control littermates, Irs1 sml /Irs1 sml (Irs1 sml/sml ) mice were small, lean, hearing impaired; had 20% less serum IGF1; were hyperinsulinemic; and were mildly insulin resistant. Irs1 sml/sml mice had low bone mineral density, reduced trabecular and cortical thicknesses, and low bone formation rates, while osteoblast and osteoclast numbers were increased in the females but not different in the males compared with the Irs1 +/+ controls. In vitro, Irs1 sml/sml bone marrow stromal cell cultures showed decreased alkaline phosphatase-positive colony forming units (pre-osteoblasts; CFU-AP+) and normal numbers of tartrate-resistant acid phosphatase-positive osteoclasts. Irs1 sml/sml stromal cells treated with IGF1 exhibited a 50% decrease in AKT phosphorylation, indicative of defective downstream signaling. Similarities between engineered knockouts and the spontaneous mutation of Irs1 sml were identified as well as significant differences with respect to heterozygosity and gender. In sum, we have identified a spontaneous mutation in the Irs1 gene associated with a major skeletal phenotype. Changes in the heterozygous Irs1 + /sml mice raise the possibility that similar mutations in humans are associated with short stature or osteoporosis.

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