Showing papers by "Dennis B. Lubahn published in 1996"
TL;DR: It is suggested that estrogen action is required for fertility in male mice and that the mutation of the ER in ERKO males leads to reduced mating frequency, low sperm numbers, and defective sperm function.
Abstract: The reproductive system of male mice homozygous for a mutation in the estrogen receptor (ER) gene (ER knock-out; ERKO) appears normal at the anatomical level. However, these males are infertile, indicating an essential role for ER-mediated processes in the regulation of male reproduction. Adult ERKO male mice have significantly fewer epididymal sperm than heterozygous or wild-type males. Although spermatogenesis is occurring in some seminiferous tubules of 3- to 5-month-old ERKO males, other tubules either have a dilated lumen and a disorganized seminiferous epithelium with few spermatogenic cells or lack a lumen and contain mainly Sertoli cells. There are no obvious differences in seminiferous tubules at 10 days of age between wild-type and ERKO mice, but the lumen in ERKO males is dilated in all seminiferous tubules by 20 days. However, spermatogenesis progresses and similar numbers of sperm are present in the cauda epididymis of ERKO and wild-type males until 10 weeks of age. Disruption of spermatogenesis and degeneration of the seminiferous tubules become apparent after 10 weeks in the caudal pole of the testis and progresses in a wave to the cranial pole by 6 months. However, the seminal vesicles, coagulating glands, prostate, and epididymis do not appear to be altered morphologically in ERKO mice. Serum testosterone levels are somewhat elevated, but LH and FSH levels are not significantly different from those in wild-type males. Sperm from 8- to 16-week-old mice have reduced motility and are ineffective at fertilizing eggs in vitro. In addition, ERKO males housed overnight with hormone-primed wild-type females produce significantly fewer copulatory plugs than do heterozygous or wild-type males. These results suggest that estrogen action is required for fertility in male mice and that the mutation of the ER in ERKO males leads to reduced mating frequency, low sperm numbers, and defective sperm function.
835 citations
Journal Article•
TL;DR: Findings from the patient and mice suggest that the absence of functional ER is not lethal, and a single patient is described who is homozygous for a point mutation in the human ER gene at codon 157, which results in estrogen insensitivity syndrome.
Abstract: The estrogen receptor (ER) is thought to play a crucial role in the regulation of many life processes, including development, reproduction and normal physiology Because there have been no known mutations of the estrogen receptor in normal tissue of humans and animals, its presence and tissue distribution is thought to be essential for survival Using the techniques of homologous recombination, we have disrupted the ER gene and have produced a line of transgenic mice possessing the altered ER gene (ERKO) The mouse ER gene was disrupted by inserting a 18 kb PGK-Neomycin sequence into exon 2, approximately 280 bp downstream of the transcription start codon The correct targeting of the disruption was demonstrated by Southern blot analysis and PCR Western blot analysis of uterine preparations from ERKO females showed no detectable ER protein Heterozygotes had one half the level of ER protein compared to wild-type animals Estrogen insensitivity was confirmed using estrogen agonists, estradiol, hydroxy tamoxifen, diethylstilbestrol treatment for 3 days which resulted in a 3-4-fold increase in uterine wet weight and vaginal cornification in wild-type females, while ERKO mice were totally unresponsive These data were further supported by the failure of estrogen or EGF treatment to induce DNA synthesis in uterine tissue of similarly treated mice Lactoferrin, an estrogen-responsive gene in the uterus, was also assayed by Northern blot Wild-type mice treated with a single estradiol injection showed a 350-fold induction in lactoferrin mRNA while ERKO females showed no detectable response Both male and female animals survive to adulthood with normal gross external phenotypes As expected, females are infertile and demonstrate hypoplastic uteri and hyperemic ovaries with no apparent corpora lutea Males are also infertile, with atrophy of the testes and seminiferous tubule dysmorphogenesis Although the reproductive capabilities have been altered with a dramatic effect on the gonads, prenatal development of the reproductive tracts of both sexes appear to be independent of an ER-mediated response Analysis of the mammary glands of the ERKO females at 4 months of age showed a primitive ductal rudiment rather than the fully developed ductal tree seen in wild-type siblings Also absent were the terminal end buds seen during normal ductal morphogenesis Both sexes show a decrease in skeletal bone density, supporting a direct role for ER action in bone A single patient is described who is homozygous for a point mutation in the human ER gene at codon 157 The mutation produces a truncation of the ER protein and results in estrogen insensitivity syndrome Most significant of the clinical findings are effects on skeletal bone density and retarded bone age Findings from the patient and mice suggest that the absence of functional ER is not lethal Mutation in the ER gene is present in the human population Further characterization of the mice and identification of additional patients will be required to more fully understand the consequences of ER gene mutations
387 citations
TL;DR: In sum, disruption of the ER gene led to a pattern of hormonal and neural changes which caused the females to lose their normal female-typical behavior and to behave and be treated more like males.
Abstract: Deficiency of normal estrogen receptor (ER) gene function led to behavioral change in female mice (ERKO females). Maternal behavior as measured by retrieving of pups was reduced. In some cases, pups w
141 citations
TL;DR: It is demonstrated that estrogen has a previously unknown role in masculine sexual development of the gubernaculum and the structures derived from it, such as the cremaster muscle.
Abstract: To determine role of estrogen receptors in testicular descent, a morphometric study of the testis and structures derived from the gubernaculum was made in sexually mature male mice having an estrogen receptor disrupted gene mutation (ERKO). Macroscopic dissections and sagittal serial sections were made of the pelvis of four wild-type mice, four mice heterozygous for the ERKO mutation, and four homozygous ERKO males. By external morphological examination the testes appeared to be descended in all three genotypes. All mice had development of a cremaster sac, which is derived from the gubernaculum, but this was twice as large in wild-type mice than in both the heterozygote or homozygote ERKO groups. The cause for the smaller cremaster sac appeared to be excessive development of the cremaster muscle in ERKO mice. The thickened muscle was associated with postmortem retraction of the testes into the inguinal canal or abdomen. Spermatogenesis and testicular volume were deficient in homozygous ERKO mice at this age. This study demonstrates that estrogen has a previously unknown role in masculine sexual development of the gubernaculum and the structures derived from it, such as the cremaster muscle.
49 citations
27 citations
TL;DR: Behavioral assay results distinguish apparent motivational performance of ERKO males from male mating reflexes: the former is similar to that of wild-type males in important respects, while the latter are deficient in ERKO male mice.
21 citations