Phenotypes associated with this allele

• Allele Symbol: Esr2^tm1Unc
• Allele Name: targeted mutation 1, University of North Carolina
• Allele ID: MGI:2152217
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Esr2^tm1Unc/Esr2^tm1Unc	B6.129P2-Esr2^tm1Unc	MGI:4418966
hm2	Esr2^tm1Unc/Esr2^tm1Unc	involves: 129P2/OlaHsd	MGI:4418758
hm3	Esr2^tm1Unc/Esr2^tm1Unc	involves: 129P2/OlaHsd * C57BL/6	MGI:3798390
hm4	Esr2^tm1Unc/Esr2^tm1Unc	involves: 129P2/OlaHsd * C57BL/6J	MGI:2174951
cx5	Esr1^tm1Ksk/Esr1^tm1Ksk Esr2^tm1Unc/Esr2^tm1Unc	involves: 129P2/OlaHsd	MGI:2664687
cx6	Esr1^tm1Ksk/Esr1^tm1Ksk Esr2^tm1Unc/Esr2^tm1Unc Inha^tm1Bay/Inha^tm1Bay	involves: 129P2/OlaHsd * 129S6/SvEvTac * 129S7/SvEvBrd	MGI:4418901
cx7	Esr1^tm1Ksk/Esr1^tm1Ksk Esr2^tm1Unc/Esr2^tm1Unc Inha^tm1Bay/Inha^+	involves: 129P2/OlaHsd * 129S6/SvEvTac * 129S7/SvEvBrd	MGI:4418903
cx8	Esr2^tm1Unc/Esr2^tm1Unc Inha^tm1Bay/Inha^tm1Bay	involves: 129P2/OlaHsd * 129S6/SvEvTac * 129S7/SvEvBrd	MGI:4418907
cx9	Esr1^tm1Ksk/Esr1^tm1Ksk Esr2^tm1Unc/Esr2^tm1Unc	involves: 129P2/OlaHsd * C57BL/6J	MGI:4398703

Genotype
MGI:4418966

hm1

• Allelic Composition: Esr2^tm1Unc/Esr2^tm1Unc
• Genetic Background: B6.129P2-Esr2^tm1Unc

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

decreased exploration in new environment ( J:101943 )

• in an elevated plus maze, mice spend less time exploring the open arms compared with wild-type mice

increased anxiety-related response ( J:101943 )

• in an elevated plus maze, mice spend less time exploring the open arms compared with wild-type mice

hyporesponsive to tactile stimuli ( J:151022 )

• female mice exhibit an increased threshold to mechanical nociception compared with similarly treated wild-type female mice

• however, male mice exhibit normal mechanical nociception

abnormal nociception after inflammation ( J:151022 )

• female mice exhibit an increased threshold to mechanical nociception following inflammation compared with similarly treated wild-type female mice

• however, male mice exhibit normal mechanical nociception after inflammation

homeostasis/metabolism

decreased dopamine level ( J:101943 )

• in the caudate putamen

decreased serotonin level ( J:101943 )

• serotonin levels are decreased in the stria terminalis, preoptic area, and hippocampus compared to in wild-type mice

Genotype
MGI:4418758

hm2

• Allelic Composition: Esr2^tm1Unc/Esr2^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:108991 )

• following induced myocardial infarction

reproductive system

abnormal mammary gland growth during pregnancy ( J:125583 )

♀ • mid-pregnancy lobuloalveolar development is not as extensive as in wild-type mice

cardiovascular system

abnormal myocardial fiber morphology ( J:93438 )

• after 8 months, the distance between myocytes is increased compared to in wild-type mice

• myofibrils exhibit irregular orientation and heterogeneous length unlike in wild-type mice

• cardiomyocytes contain abnormal nuclear envelops

abnormal intercalated disk morphology ( J:93438 )

• intercalating disks are more convoluted than in wild-type hearts with greater membrane lengths

increased myocardial fiber size ( J:93438 )

• after 8 months, the diameter of myocytes is increased compared to in wild-type mice

enlarged heart ( J:93438 )

• after 8 months

increased heart weight ( J:108991 )

• in sham-operated mice

cardiac hypertrophy ( J:93438 )

• after 8 months, mice exhibit ventricular hypertrophy compared with wild-type mice

dilated heart ventricle ( J:93438 )

• after 8 months

abnormal response to cardiac infarction ( J:108991 )

• following induced myocardial infarction, mice exhibit increased body weight and mortality, pleural effusions, and ascites compared with similarly treated wild-type mice

• however, infarct size is normal

increased vasodilation ( J:64165 )

• 17beta-estradiol-induced relaxation of aortic rings is more pronounced than in similarly treated wild-type rings

digestive/alimentary system

abnormal enterocyte morphology ( J:107308 )

• colonic epithelium cells exhibit abnormal tight junctions and desmosomes compared to in wild-type mice

• colonic epithelial cells exhibit reduced expression of differentiation markers compared to in wild-type mice

abnormal large intestine crypts of Lieberkuhn morphology ( J:107308 )

• in the distal colon, mucin appears as large globs in the upper crypts and on top of the crypts unlike in wild-type mice

• however, mice exhibit normal crypt length, crypt area, nuclear density, number of cells per crypt, and occurrence of aberrant crypt foci

abnormal enterocyte physiology ( J:107308 )

• colonic cells exhibit increased migration to the luminal surface compared with wild-type mice

decreased enterocyte apoptosis ( J:107308 )

• a few apoptotic cells are found in the colonic epithelium compared to in wild-type mice

abnormal enterocyte proliferation ( J:107308 )

• colonic cells exhibit a 1.6-fold higher than in wild-type mice

colitis ( J:107308 )

• at 4 months, mice exhibit lymphoid infiltration below the epithelium in the colon unlike wild-type mice

• however, lymphoid infiltration at 12 months is less severe

homeostasis/metabolism

abnormal response to cardiac infarction ( J:108991 )

• following induced myocardial infarction, mice exhibit increased body weight and mortality, pleural effusions, and ascites compared with similarly treated wild-type mice

• however, infarct size is normal

decreased insulin secretion ( J:151012 )

• following glucose stimulation, peak insulin secretion is delayed compared to in similarly treated wild-type mice

decreased circulating glucose level ( J:151012 )

• in fasting mice prior to and after tamoxifen treatment

increased circulating glucose level ( J:151012 )

• in fed mice

ascites ( J:108991 )

• following induced myocardial infarction

increased insulin sensitivity ( J:151012 )

increased urine glycosaminoglycan level ( J:122274 )

• female mice exhibit an increase in urinary glycosaminoglycan content compared with wild-type mice

• however, male mice have normal urine glycosaminoglycan content

abnormal response/metabolism to endogenous compounds ( J:64165 )

• 17beta-estradiol-induced relaxation of aortic rings is more pronounced than in similarly treated wild-type rings

respiratory system

abnormal pulmonary alveolus morphology ( J:89974 )

• female, but not male, 3 month old mice exhibit larger and fewer alveoli compared with wild-type mice

• female mice exhibit an accumulation of surfactant inside the alveolar spaces unlike in wild-type mice

• however, lung alveoli morphology is normal at P14 and 4 weeks

abnormal surfactant physiology ( J:89974 )

• female mice exhibit an accumulation of surfactant inside the alveolar spaces unlike in wild-type mice

muscle

abnormal myocardial fiber morphology ( J:93438 )

• after 8 months, the distance between myocytes is increased compared to in wild-type mice

• myofibrils exhibit irregular orientation and heterogeneous length unlike in wild-type mice

• cardiomyocytes contain abnormal nuclear envelops

abnormal intercalated disk morphology ( J:93438 )

• intercalating disks are more convoluted than in wild-type hearts with greater membrane lengths

increased myocardial fiber size ( J:93438 )

• after 8 months, the diameter of myocytes is increased compared to in wild-type mice

increased vasodilation ( J:64165 )

• 17beta-estradiol-induced relaxation of aortic rings is more pronounced than in similarly treated wild-type rings

abnormal muscle contractility ( J:95398 )

• during fatiguing stimulation, male mice exhibit less of a decrease in force compared with similarly treated wild-type mice

• during recovery from fatiguing stimulation, male mice exhibit higher force generation than similarly treated wild-type mice

renal/urinary system

increased urine glycosaminoglycan level ( J:122274 )

• female mice exhibit an increase in urinary glycosaminoglycan content compared with wild-type mice

• however, male mice have normal urine glycosaminoglycan content

abnormal urinary bladder morphology ( J:122274 )

• at 8 months, female mice exhibit epithelial atrophy, massive ulceration of the bladder, and invasion of immune cells into the stroma and epithelium unlike in wild-type mice

• however, bladders of male mice are normal

abnormal urinary bladder urothelium morphology ( J:122274 )

• female mice exhibit ulceration and atrophy of bladder urothelium unlike in wild-type mice

abnormal urinary bladder physiology ( J:122274 )

• bladder permeability in female mice is higher than in wild-type mice

urinary bladder inflammation ( J:122274 )

• female mice exhibit an increase in T cell and macrophage infiltration in the female bladders unlike in wild-type mice

limbs/digits/tail

long femur ( J:111108 )

• at 2 and 4, but not 18, months

skeleton

long femur ( J:111108 )

• at 2 and 4, but not 18, months

abnormal long bone epiphyseal plate morphology ( J:111108 )

• the number of proliferative chondrocytes per column is increased while the number of hypertrophic chondrocytes per column is decreased compared to in wild-type mice

behavior/neurological

abnormal behavior ( J:151012 )

• when suspended by their tails, fasted mice exhibit tremulousness, disturbed gait and balance, and spinning movement unlike similarly treated wild-type mice

impaired contextual conditioning behavior ( J:115451 )

• during fear conditioning, mice exhibit an impairment in memory for context compared with wild-type mice

impaired cued conditioning behavior ( J:115451 )

• in male mice

nervous system

abnormal excitatory postsynaptic potential ( J:115451 )

• female mice exhibit poorer fast synaptic transmission compared with wild-type mice

reduced long-term potentiation ( J:115451 )

• in female mice

endocrine/exocrine glands

abnormal large intestine crypts of Lieberkuhn morphology ( J:107308 )

• in the distal colon, mucin appears as large globs in the upper crypts and on top of the crypts unlike in wild-type mice

• however, mice exhibit normal crypt length, crypt area, nuclear density, number of cells per crypt, and occurrence of aberrant crypt foci

enlarged pancreatic islets ( J:151012 )

• the average islet area is larger than in wild-type mice

• mice exhibit a reduction in the percent of small islets and an increase in the percent of larger islets compared to in wild-type mice

abnormal mammary gland growth during lactation ( J:125583 )

♀ • on day 6 of lactation, lobuloalveolar development only partially penetrates the fat pad and the alveoli are enlarged unlike in wild-type mice

abnormal mammary gland growth during pregnancy ( J:125583 )

♀ • mid-pregnancy lobuloalveolar development is not as extensive as in wild-type mice

abnormal mammary gland epithelium morphology ( J:125583 )

♀ • at day 6 of lactation, mammary gland exhibits increased visible adipose tissue and reduced epithelium compared to in wild-type mice

mammary gland alveolar hyperplasia ( J:125583 )

♀ • on day 6 of lactation

decreased insulin secretion ( J:151012 )

• following glucose stimulation, peak insulin secretion is delayed compared to in similarly treated wild-type mice

immune system

colitis ( J:107308 )

• at 4 months, mice exhibit lymphoid infiltration below the epithelium in the colon unlike wild-type mice

• however, lymphoid infiltration at 12 months is less severe

urinary bladder inflammation ( J:122274 )

• female mice exhibit an increase in T cell and macrophage infiltration in the female bladders unlike in wild-type mice

growth/size/body

enlarged heart ( J:93438 )

• after 8 months

increased heart weight ( J:108991 )

• in sham-operated mice

cardiac hypertrophy ( J:93438 )

• after 8 months, mice exhibit ventricular hypertrophy compared with wild-type mice

increased body weight ( J:108991 )

• following induced myocardial infarction

increased body length ( J:111108 )

• at 4, but not 18, months

hearing/vestibular/ear

abnormal auditory brainstem response ( J:135833 )

• following accoustic trauma, mice exhibit a greater shift in brainstem auditory evoked potential compared with similarly treated wild-type mice

integument

abnormal mammary gland growth during lactation ( J:125583 )

♀ • on day 6 of lactation, lobuloalveolar development only partially penetrates the fat pad and the alveoli are enlarged unlike in wild-type mice

abnormal mammary gland growth during pregnancy ( J:125583 )

♀ • mid-pregnancy lobuloalveolar development is not as extensive as in wild-type mice

abnormal mammary gland epithelium morphology ( J:125583 )

♀ • at day 6 of lactation, mammary gland exhibits increased visible adipose tissue and reduced epithelium compared to in wild-type mice

mammary gland alveolar hyperplasia ( J:125583 )

♀ • on day 6 of lactation

cellular

decreased enterocyte apoptosis ( J:107308 )

• a few apoptotic cells are found in the colonic epithelium compared to in wild-type mice

abnormal enterocyte proliferation ( J:107308 )

• colonic cells exhibit a 1.6-fold higher than in wild-type mice

Genotype
MGI:3798390

hm3

• Allelic Composition: Esr2^tm1Unc/Esr2^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

homeostasis/metabolism

abnormal response of heart to induced stress ( J:101968 )

• female mice treated with isoproterenol prior to ischemia, exhibit less recovery of postischemic function compared with similarly treated wild-type mice

increased circulating luteinizing hormone level ( J:118736 )

• higher than normal luteinizing hormone levels are further elevated by ovariectomy

decreased physiological sensitivity to xenobiotic ( J:101968 )

• female mice treated with isoproterenol prior to ischemia, exhibit less recovery of postischemic function, phosphocreatine, and ATP compared with similarly treated wild-type mice

cardiovascular system

abnormal response of heart to induced stress ( J:101968 )

• female mice treated with isoproterenol prior to ischemia, exhibit less recovery of postischemic function compared with similarly treated wild-type mice

Genotype
MGI:2174951

hm4

• Allelic Composition: Esr2^tm1Unc/Esr2^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

reproductive system

reproductive system phenotype ( J:51663 )

N • at 7-9 weeks of age, female homozygotes display normal mammary gland histology and appear to lactate efficiently, as judged by normal nursing behavior and growth of their pups

prostate gland epithelial hyperplasia ( J:51663 )

♂ • at >3 months of age, male homozygotes exhibit epithelial hyperplasia in the prostatic collecting ducts

decreased corpora lutea number ( J:51663 )

♀ • at 7-9 weeks of age, young adult female homozygotes display ovaries with less corpora lutea relative to wild-type mice

♀ • upon superovulation, ovaries from immature (25-31 days) female homozygotes display fewer corpora lutea than ovaries from stimulated wild-type females

abnormal cumulus oophorus morphology ( J:51663 )

♀ • upon superovulation, immature (25-31 days) female homozygotes display a reduction in the cellular mass of the oocyte cumulus relative to wild-type and heterozygous littermates

increased atretic ovarian follicle number ( J:51663 )

♀ • more early atretic follicles at 7-9 weeks of age

impaired ovarian folliculogenesis ( J:51663 )

♀ • at 7-9 weeks of age, young adult female homozygotes display ovaries with more early atretic follicles and fewer corpora lutea relative to wild-type mice, suggesting partial arrest of follicular development and less frequent follicular maturation

abnormal superovulation ( J:51663 )

♀ • ovaries from superovulated immature female homozygotes display a large number of mature oocytes, indicating a normal response to pregnant mare serum gonadotropin, but contain less corpora lutea than stimulated wild-type ovaries, suggesting that some follicles fail to fully respond and discharge their oocytes in response to hCG

decreased superovulation rate ( J:51663 )

♀ • upon superovulation, immature (25-31 days) female homozygotes display an average yield of 6.0 +/- 1.5 oocytes per female, whereas wild-type and heterozygous females yield 33.7 +/- 4.8 and 52.5 +/- 5.7 oocytes per female, respectively

failure of superovulation ( J:51663 )

♀ • upon superovulation, 2 of 11 immature (25-31 days) female homozygotes yield no detectable ova

reduced female fertility ( J:51663 )

♀ • female homozygotes show normal sexual behavior but produce significantly fewer litters than wild-type females (1.7 +/- 1.0 vs 2.8 +/- 0.4 litters/female, respectively)

♀ • in contrast, young, sexually mature male homozygotes reproduce normally

decreased litter size ( J:51663 )

• female homozygotes show a significantly reduced litter size relative to wild-type females (3.1 +/- 1.8 vs 8.8 +/- 2.5 pups/litter, respectively)

growth/size/body

enlarged liver ( J:83617 )

• with leukocyte, mainly granulocytes with some B lymphocytes, infiltration

enlarged spleen ( J:83617 )

• profound by 1.5 years of age with leukocyte infiltration

spleen hyperplasia ( J:83617 )

nervous system

abnormal cochlear IHC afferent innervation pattern ( J:108892 )

• at 2-6 months of age, female homozygotes exhibit some dilated afferent nerve endings on the cochlear IHCs, in the absence of a swollen stria vascularis

• however, middle and inner ear morphology is relatively normal relative to heterozygotes, and positive estrogen receptor alpha immunostaining is noted at the same locations as in control CBA/Ca mice

decreased brain size ( J:67862 )

• at 2 years of age, mutant brains are significantly smaller than wild-type, exhibiting obvious atrophy in the somatosensory-parietal cortex

• however, no differences in overall brain size are observed at 2 months or at 1 year of age

abnormal substantia nigra morphology ( J:67862 )

• by 2 yrs of age, homozygotes exhibit severe degeneration of neuronal cell bodies in the substantia nigra

abnormal neocortex morphology ( J:67862 )

• at 2 months of age, homozygotes display hypocellularity of the neocortex, with severe neuronal deficit in layers II, III, IV and V, extending from the somatosensory region to the parietal region

abnormal somatosensory cortex morphology ( J:67862 )

• at 2 months of age, homozygotes display a significant reduction in the number of neurons in layer II, III, IV, and V of the somatosensory cortex

• by 2 years of age, an obvious atrophy affecting all layers is noted in the somatosensory-parietal cortex; however, thinning of layers IV and V is particularly pronounced

abnormal astrocyte morphology ( J:67862 )

• at 2 months of age, male homozygotes display hypertrophic astroglial cells, with swollen cell bodies and thicker processes relative to wild-type mice

• at 2 months of age, an increase in the number of hypertrophic astrocytes is also observed in the white matter adjacent to regions of neuronal loss

• at 1 year of age, both male and female homozygotes show a mild to moderate increase in the number of astrocytes relative to wild-type counterparts; however, no significant differences in the number or morphology of GFAP immunoreactive cells are observed at 2 years of age

astrocytosis ( J:67862 )

• at 2 months of age, male homozygotes show an increased number of GFAP-immunoreactive cells throughout many brain areas, esp. in the basal forebrain, hypothalamus, and amygdala; females are less affected than males

• only a mild increase of GFAP immunoreactivity is detected in the hippocampus and cerebellum

• strikingly, no astrogliosis is observed in regions of the somatosensory cortex with severe neuronal loss

decreased neuron number ( J:67862 )

• at 2 months of age, homozygotes display a severe neuronal deficit in layers II, III, IV and V of the neocortex, as well as significant neuronal loss in the basal forebrain, hypothalamus, amygdala, ventral tegmental area, substantia nigra, central gray, dorsal raphe nucleus, locus coeruleus, solitary tract nucleus, medial preoptic area, and medial amygdala nucleus

• at 2 months of age, neuronal loss is much more pronounced in male than in female homozygotes

• at 1 year of age, both male and female homozygotes exhibit neuronal hypocellularity in the same brain regions, but the overall brain size is still similar to that of wild-type counterparts

• at 2 years of age, homozygotes show a decreased number of small neurons in layers II, III, IV, and V of the somatosensory cortex, as well as loss of large pyramidal neurons in layer V

• no obvious neuronal deficit is found in the paraventricular nucleus of hypothalamus (PVN), hippocampus, caudate-putamen, thalamus, or cerebellum at 2 months of age or later

neuron degeneration ( J:67862 )

• at 2 yrs of age, homozygotes exhibit degeneration of neuronal cell bodies throughout the brain, esp. in the substantia nigra

• however, no shrinkage of neuronal cell bodies is noted in mutant brains at 2 months of age

• no neurofibrillary tangles or Lewy bodies are ever observed, even at 2 yrs of age

immune system

enlarged spleen ( J:83617 )

• profound by 1.5 years of age with leukocyte infiltration

spleen hyperplasia ( J:83617 )

abnormal leukopoiesis ( J:83617 )

• granulopoiesis is enhanced compared to in wild-type mice

abnormal lymphopoiesis ( J:83617 )

• at 1.5 years, some mice exhibit lymphoid blast crisis unlike in wild-type mice

increased pro-B cell number ( J:83617 )

abnormal B cell number ( J:82423 )

• 17beta-estradiol-treated castrated mice exhibit a reduced decrease in the frequency of B cells compared with similarly treated wild-type mice

• 17beta-estradiol-treated castrated mice fail to exhibit a decrease in newly formed B cells unlike similarly treated wild-type mice

• however, 17beta-estradiol-treated castrated mice exhibit decreases in pre-B and pro-B cells

increased pre-B cell number ( J:83617 )

increased leukocyte cell number ( J:83617 )

• at 1.5 years, leukocyte numbers in the blood is increased 3- to 4-fold compared to in wild-type mice

increased granulocyte number ( J:83617 )

• granulocyte populations in the bone marrow are increased 15% to 30% compared to in wild-type mice

• absolute numbers of granulocytes are increased 2-fold compared to in wild-type mice

increased neutrophil cell number ( J:83617 )

• in the blood at 1.5 years of age

increased monocyte cell number ( J:83617 )

• in the blood at 1.5 years of age

spleen hypoplasia ( J:110416 )

• 17beta-estradiol-treated ovariectomized mice exhibit a reduction in spleen cellularity unlike similarly treated wild-type mice

enlarged lymph nodes ( J:83617 )

• by 1.5 years of age

cardiovascular system

abnormal vascular smooth muscle morphology ( J:73898 )

• vascular smooth muscle cells are half normal size

increased systemic arterial blood pressure ( J:73898 )

• increased blood pressure in most mice at 6-7 months of age

• blood pressure remains elevated to 22 months of age

• heart rate unchanged

abnormal vascular smooth muscle physiology ( J:73898 )

• absence of voltage dependent outward current

increased vasoconstriction ( J:73898 )

skeleton

skeleton phenotype ( J:62222 )

N • unlike in Esr1 null mice, no defects are detected in the skeletal system

myelofibrosis ( J:83617 )

• at 2 years, mice develop myelofibrosis unlike wild-type mice

increased compact bone area ( J:91765 )

• load-induced increase in cortical area is reduced 2-fold compared to in similarly treated wild-type mice

increased osteoblast cell number ( J:91765 )

• after 10 minutes of mechanical stress, the number of osteoblast-like cells is increased more than in similarly treated wild-type mice

abnormal bone mineralization ( J:91765 )

• load-induced increase in periosteal mineralization is decreased 50% compared to in similarly treated wild-type mice

endocrine/exocrine glands

prostate gland epithelial hyperplasia ( J:51663 )

♂ • at >3 months of age, male homozygotes exhibit epithelial hyperplasia in the prostatic collecting ducts

decreased corpora lutea number ( J:51663 )

♀ • at 7-9 weeks of age, young adult female homozygotes display ovaries with less corpora lutea relative to wild-type mice

♀ • upon superovulation, ovaries from immature (25-31 days) female homozygotes display fewer corpora lutea than ovaries from stimulated wild-type females

abnormal cumulus oophorus morphology ( J:51663 )

♀ • upon superovulation, immature (25-31 days) female homozygotes display a reduction in the cellular mass of the oocyte cumulus relative to wild-type and heterozygous littermates

increased atretic ovarian follicle number ( J:51663 )

♀ • more early atretic follicles at 7-9 weeks of age

impaired ovarian folliculogenesis ( J:51663 )

♀ • at 7-9 weeks of age, young adult female homozygotes display ovaries with more early atretic follicles and fewer corpora lutea relative to wild-type mice, suggesting partial arrest of follicular development and less frequent follicular maturation

hearing/vestibular/ear

abnormal cochlear IHC afferent innervation pattern ( J:108892 )

• at 2-6 months of age, female homozygotes exhibit some dilated afferent nerve endings on the cochlear IHCs, in the absence of a swollen stria vascularis

• however, middle and inner ear morphology is relatively normal relative to heterozygotes, and positive estrogen receptor alpha immunostaining is noted at the same locations as in control CBA/Ca mice

renal/urinary system

abnormal urinary bladder urothelium morphology ( J:51663 )

• at >3 months of age, male homozygotes exhibit epithelial hyperplasia in the bladder wall

muscle

abnormal vascular smooth muscle morphology ( J:73898 )

• vascular smooth muscle cells are half normal size

abnormal vascular smooth muscle physiology ( J:73898 )

• absence of voltage dependent outward current

increased vasoconstriction ( J:73898 )

abnormal muscle electrophysiology ( J:73898 )

• absence of voltage dependent outward current in vascular smooth muscle cells

hematopoietic system

enlarged spleen ( J:83617 )

• profound by 1.5 years of age with leukocyte infiltration

spleen hyperplasia ( J:83617 )

abnormal leukopoiesis ( J:83617 )

• granulopoiesis is enhanced compared to in wild-type mice

abnormal lymphopoiesis ( J:83617 )

• at 1.5 years, some mice exhibit lymphoid blast crisis unlike in wild-type mice

increased pro-B cell number ( J:83617 )

anemia ( J:83617 )

• at 2 years in surviving mice

abnormal bone marrow cell number ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit a decrease in bone marrow cellularity unlike similarly treated wild-type mice

increased bone marrow cell number ( J:83617 )

• as early as 1 month of age

increased megakaryocyte cell number ( J:83617 )

• in the spleen and bone marrow

increased erythrocyte cell number ( J:83617 )

• at 2 years, mice exhibit accumulation of red blood cells unlike in wild-type mice

abnormal B cell number ( J:82423 )

• 17beta-estradiol-treated castrated mice exhibit a reduced decrease in the frequency of B cells compared with similarly treated wild-type mice

• 17beta-estradiol-treated castrated mice fail to exhibit a decrease in newly formed B cells unlike similarly treated wild-type mice

• however, 17beta-estradiol-treated castrated mice exhibit decreases in pre-B and pro-B cells

increased pre-B cell number ( J:83617 )

increased leukocyte cell number ( J:83617 )

• at 1.5 years, leukocyte numbers in the blood is increased 3- to 4-fold compared to in wild-type mice

increased granulocyte number ( J:83617 )

• granulocyte populations in the bone marrow are increased 15% to 30% compared to in wild-type mice

• absolute numbers of granulocytes are increased 2-fold compared to in wild-type mice

increased neutrophil cell number ( J:83617 )

• in the blood at 1.5 years of age

increased monocyte cell number ( J:83617 )

• in the blood at 1.5 years of age

spleen hypoplasia ( J:110416 )

• 17beta-estradiol-treated ovariectomized mice exhibit a reduction in spleen cellularity unlike similarly treated wild-type mice

homeostasis/metabolism

increased circulating insulin-like growth factor I level ( J:110416 )

• 17beta-estradiol-treated ovariectomized mice fail to exhibit a reduction in IGF-1 serum levels unlike similarly treated wild-type mice

abnormal response/metabolism to endogenous compounds ( J:82423 , J:110416 )

• 17beta-estradiol-treated castrated mice fail to exhibit a decrease in bone marrow cellularity and exhibit a reduced decrease in the frequency of B cells unlike similarly treated wild-type mice (J:82423)

• however, 17beta-estradiol-treated castrated mice exhibit immunoglobulin switching and increased immunoglobulin levels (J:82423)

• 17beta-estradiol-treated ovariectomized mice fail to exhibit a reduction in the cortex area ration of the thymus, alterations in thymocyte frequencies, or reduced IGF-1 serum levels unlike similarly treated wild-type mice (J:110416)

• 17beta-estradiol-treated ovariectomized mice exhibit a reduction in spleen cellularity unlike similarly treated wild-type mice (J:110416)

• however, 17beta-estradiol-treated ovariectomized mice exhibit normal reduction in thymus weight and cellularity (J:110416)

behavior/neurological

behavior/neurological phenotype ( J:65785 )

N • unlike mice null for Esr1, no defect in retention is detected in an inhibitory avoidance behavior assay

abnormal spatial learning ( J:75472 )

• ovariectomized mice exhibit slower escape time from a Morris water maze compared with similarly treated wild-type mice

• ovariectomized mice treated with 17beta-estradiol exhibit reduced escape platform learning in a Morris water maze compared with similarly treated wild-type mice

• however, ovariectomized mice treated with 17beta-estradiol exhibit normal escape from a cued water maze

increased aggression towards male mice ( J:66582 )

• in a resident intruder assay aggressive behaviors toward the intruder male are increased in the first trial but not in subsequent trials compared to wild-type controls

• younger mice and naive (not used in sexual behavior assays) mice display increased aggression compared to wild-type controls

abnormal sexual interaction ( J:66582 )

♂ • in a 90 min test with a receptive female the number of mounts is decreased; however, the ratio of mounts and intromissions to ejaculations is reduced indicating increased sexual excitement

liver/biliary system

enlarged liver ( J:83617 )

• with leukocyte, mainly granulocytes with some B lymphocytes, infiltration

respiratory system

abnormal lung morphology ( J:83617 )

• lungs contain leukocyte, mainly granulocytes with some B lymphocytes, macrophages and eosinophils, infiltration unlike in wild-type mice

neoplasm

increased chronic myelocytic leukemia incidence ( J:83617 )

• mice exhibit a myeloproliferative disease with granulocytosis and massive blast cell infiltration of hematopoietic and nonhematopoietic organs

integument

increased keratinocyte apoptosis ( J:107589 )

• in hair matrix keratinocytes

abnormal hair cycle catagen phase ( J:107589 )

• at P17 and P19, more hair follicles are in catagen than in wild-type mice

accelerated hair follicle regression ( J:107589 )

• apoptosis of hair follicle and hair matrix keratinocyte is increased compared to in wild-type mice confirming accelerated apoptosis-driven hair follicle regression

thin epidermis ( J:107589 )

• dermal thickness is less than in wild-type mice

cellular

increased keratinocyte apoptosis ( J:107589 )

• in hair matrix keratinocytes

Genotype
MGI:2664687

cx5

• Allelic Composition: Esr1^tm1Ksk/Esr1^tm1Ksk; Esr2^tm1Unc/Esr2^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd

reproductive system

oligozoospermia ( J:59105 )

♂ • 80% reduction in epididymal sperm count relative to wild-type

asthenozoospermia ( J:59105 )

♂ • 5% reduction in the motility of sperm obtained from the epididymis

abnormal ovary morphology ( J:59105 )

♀ • postnatal transdifferentiation of portions of the ovary, resulting in structures resembling seminiferous tubules

♀ • these tubule-like structures contained degenerating granulosa cells, sertoli-like cells, and in some cases, degenerating oocytes

absent corpus luteum ( J:59105 )

♀

uterus hypoplasia ( J:59105 )

♀ • evident at 2.5 to 7 months of age

♀ • however, normal development of Mullerian-derived structures (uterus, cervix, and upper vagina) is seen

female infertility ( J:59105 )

♀

male infertility ( J:59105 )

♂

skeleton

long femur ( J:111108 )

• at 4, 9, and 18 months, femur length is increased compared to in Esr1^tm1Ksk homozygotes

abnormal vertebrae morphology ( J:111108 )

• at 18 months, vertebra height is increased compared to in to Esr1^tm1Ksk homozygotes

endocrine/exocrine glands

abnormal ovary morphology ( J:59105 )

♀ • postnatal transdifferentiation of portions of the ovary, resulting in structures resembling seminiferous tubules

♀ • these tubule-like structures contained degenerating granulosa cells, sertoli-like cells, and in some cases, degenerating oocytes

absent corpus luteum ( J:59105 )

♀

homeostasis/metabolism

increased circulating luteinizing hormone level ( J:59105 )

• higher than those observed in Esr1^tm1Ksk homozygous mice

growth/size/body

increased body length ( J:111108 )

• at 9 and 18 months, crown to rump length is increased compared to Esr1^tm1Ksk homozygotes

limbs/digits/tail

long femur ( J:111108 )

• at 4, 9, and 18 months, femur length is increased compared to in Esr1^tm1Ksk homozygotes

cellular

oligozoospermia ( J:59105 )

♂ • 80% reduction in epididymal sperm count relative to wild-type

asthenozoospermia ( J:59105 )

♂ • 5% reduction in the motility of sperm obtained from the epididymis

Genotype
MGI:4418901

cx6

• Allelic Composition: Esr1^tm1Ksk/Esr1^tm1Ksk; Esr2^tm1Unc/Esr2^tm1Unc; Inha^tm1Bay/Inha^tm1Bay
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * 129S7/SvEvBrd

mortality/aging

premature death ( J:84989 )

• most female mice die between 4 and 6 weeks of age and all die by 9 weeks of age

• male mice survival 19 weeks

reproductive system

decreased male germ cell number ( J:84989 )

♂ • male germ cells are depleted and degenerated

abnormal ovary morphology ( J:84989 )

♀ • tubule-like structures resembling Sertoli-like cells are found adjacent to tumor unlike in wild-type mice

abnormal seminiferous tubule morphology ( J:84989 )

♂ • tubule lumens are filled with Sertoli cells unlike in wild-type mice

dilated seminiferous tubule ( J:84989 )

♂

increased ovary tumor incidence ( J:84989 )

♀ • mice develop aggressive bilateral ovarian tumors with hemorrhagic foci

♀ • tumors contain granulosa-like cells

increased testis tumor incidence ( J:84989 )

♂ • mice develop testicular tumors formed of granulosa-like cells with numerous sites of hemorrhage

♂ • mice fail to develop early Sertoli cells unlike in Esr1^tm1Ksk Inha^tm1Bay or Esr2^tm1Unc Inha^tm1Bay double homozygotes

neoplasm

increased ovary tumor incidence ( J:84989 )

♀ • mice develop aggressive bilateral ovarian tumors with hemorrhagic foci

♀ • tumors contain granulosa-like cells

increased testis tumor incidence ( J:84989 )

♂ • mice develop testicular tumors formed of granulosa-like cells with numerous sites of hemorrhage

♂ • mice fail to develop early Sertoli cells unlike in Esr1^tm1Ksk Inha^tm1Bay or Esr2^tm1Unc Inha^tm1Bay double homozygotes

growth/size/body

decreased body weight ( J:84989 )

• compared with Esr1^tm1Ksk and Esr2^tm1Unc single homozygotes

cachexia ( J:84989 )

• at 26 weeks

increased body weight ( J:84989 )

• compared to in Inha^tm1Bay

homeostasis/metabolism

decreased circulating follicle stimulating hormone level ( J:84989 )

endocrine/exocrine glands

abnormal ovary morphology ( J:84989 )

♀ • tubule-like structures resembling Sertoli-like cells are found adjacent to tumor unlike in wild-type mice

abnormal seminiferous tubule morphology ( J:84989 )

♂ • tubule lumens are filled with Sertoli cells unlike in wild-type mice

dilated seminiferous tubule ( J:84989 )

♂

increased ovary tumor incidence ( J:84989 )

♀ • mice develop aggressive bilateral ovarian tumors with hemorrhagic foci

♀ • tumors contain granulosa-like cells

increased testis tumor incidence ( J:84989 )

♂ • mice develop testicular tumors formed of granulosa-like cells with numerous sites of hemorrhage

♂ • mice fail to develop early Sertoli cells unlike in Esr1^tm1Ksk Inha^tm1Bay or Esr2^tm1Unc Inha^tm1Bay double homozygotes

cellular

decreased male germ cell number ( J:84989 )

♂ • male germ cells are depleted and degenerated

Genotype
MGI:4418903

cx7

• Allelic Composition: Esr1^tm1Ksk/Esr1^tm1Ksk; Esr2^tm1Unc/Esr2^tm1Unc; Inha^tm1Bay/Inha⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * 129S7/SvEvBrd

reproductive system

abnormal ovary morphology ( J:84989 )

♀ • ovaries develop tubule-like structures unlike in wild-type mice

increased ovary tumor incidence ( J:84989 )

♀ • in one mouse

neoplasm

increased ovary tumor incidence ( J:84989 )

♀ • in one mouse

endocrine/exocrine glands

abnormal ovary morphology ( J:84989 )

♀ • ovaries develop tubule-like structures unlike in wild-type mice

increased ovary tumor incidence ( J:84989 )

♀ • in one mouse

Genotype
MGI:4418907

cx8

• Allelic Composition: Esr2^tm1Unc/Esr2^tm1Unc; Inha^tm1Bay/Inha^tm1Bay
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * 129S7/SvEvBrd

mortality/aging

premature death ( J:84989 )

• all mice die by 20 weeks of age similar to Inha^tm1Bay homozygotes

neoplasm

increased ovary tumor incidence ( J:84989 )

♀ • similar to Inha^tm1Bay homozygotes

increased testis tumor incidence ( J:84989 )

♂ • similar to Inha^tm1Bay homozygotes

digestive/alimentary system

abnormal stomach morphology ( J:84989 )

• mice develop hallmarks of disease progression that are similar to in Inha^tm1Bay homozygotes

growth/size/body

cachexia ( J:84989 )

• similar to Inha^tm1Bay homozygotes

liver/biliary system

abnormal liver morphology ( J:84989 )

• mice develop hallmarks of disease progression that are similar to in Inha^tm1Bay homozygotes

endocrine/exocrine glands

increased ovary tumor incidence ( J:84989 )

♀ • similar to Inha^tm1Bay homozygotes

increased testis tumor incidence ( J:84989 )

♂ • similar to Inha^tm1Bay homozygotes

reproductive system

increased ovary tumor incidence ( J:84989 )

♀ • similar to Inha^tm1Bay homozygotes

increased testis tumor incidence ( J:84989 )

♂ • similar to Inha^tm1Bay homozygotes

Genotype
MGI:4398703

cx9

• Allelic Composition: Esr1^tm1Ksk/Esr1^tm1Ksk; Esr2^tm1Unc/Esr2^tm1Unc
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

reproductive system

abnormal uterus weight ( J:115411 )

♀ • 17beta-estradiol-induced increase in uterus weight is less than in similarly treated wild-type mice

decreased uterus weight ( J:115411 )

♀

failure of ejaculation ( J:66582 )

♂ • during a 30 min interaction with a receptive female males failed to show any ejaculations

behavior/neurological

decreased aggression towards male mice ( J:66582 )

• in a resident intruder assay aggressive behaviors toward the intruder male are greatly reduced and mice rarely show offensive attacks

• loss of offensive attacks is also seen when males are tested in a neutral cage

increased aggression towards female mice ( J:66582 )

• about 50% of males display defensive type aggression towards receptive females

abnormal sexual interaction ( J:66582 )

♂ • during a 30 min interaction with a receptive female males failed to show any ultrasonic vocalizations, mounts, intromissions, or ejaculations

♂ • similar results are seen when the interaction is extended to 90 min

skeleton

short femur ( J:62222 )

• in post-pubertal mice

decreased bone mineral content ( J:62222 )

• bone mineral content normalized to body weight is decreased in the total body, femur and spine

decreased areal bone mineral density ( J:62222 )

• total areal bone mineral density is slightly decreased in adults

decreased bone mineral density of femur ( J:62222 )

• femur bone mineral density is decreased in adults

decreased compact bone area ( J:62222 )

• decrease in mid-diaphyseal bone mineral content in the femur and tibia mainly as a result of a decrease in cross-sectional area associated with a decrease in periosteal and endosteal circumference

decreased femoral compact bone area ( J:62222 )

homeostasis/metabolism

decreased circulating insulin-like growth factor I level ( J:62222 )

increased circulating leptin level ( J:66077 )

• in males at 4 months of age but not at 1 or 2 months of age

decreased circulating osteocalcin level ( J:62222 )

• decrease in the concentration of osteocalcin, a marker of bone formation, in the serum at 110 days of age

increased circulating cholesterol level ( J:66077 )

• in adult males

increased circulating HDL cholesterol level ( J:66077 )

• in adult males

insulin resistance ( J:66077 )

• in males at 4 months of age the insulin x free fatty acid product is increased suggesting the mice are insulin resistant

abnormal response/metabolism to endogenous compounds ( J:82423 , J:115411 )

• 17beta-estradiol-treated castrated mice fail to exhibit a decrease in bone marrow cellularity, a reduced decrease in the frequency of B cells, immunoglobulin switching, or an increase in production of immunoglobulins (IgA, IgG, and IgM) unlike similarly treated wild-type mice (J:82423)

• 17beta-estradiol-induced increase in uterus weight is less than in similarly treated wild-type mice (J:115411)

• treatment with 17beta-estradiol fails to inhibit vascular injury-induced increases in medial area unlike in similarly treated wild-type mice (J:115411)

• however, vascular smooth muscle cell proliferation following injury and 17beta-estradiol treatment is normal (J:115411)

growth/size/body

decreased body weight ( J:62222 )

• late pubertal and young adult body weight is decreased compared to controls

obese ( J:66077 )

• males at 4 months of age are obese

limbs/digits/tail

decreased femoral compact bone area ( J:62222 )

short femur ( J:62222 )

• in post-pubertal mice

immune system

thymus hypoplasia ( J:110416 )

abnormal class switch recombination ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit immunoglobulin switching unlike similarly treated wild-type mice

increased double-positive T cell number ( J:110416 )

• mice have increased double positive CD4+CD8+ thymocytes compared to in wild-type mice

abnormal B cell number ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit a reduced decrease in the frequency of B cells (including pre-B cells, pro-B cells, and newly formed B cells) compared with similarly treated wild-type mice

decreased CD4-positive, alpha-beta T cell number ( J:110416 )

• mice have fewer single positive CD4+ and CD8+ thymocytes compared to in wild-type mice

decreased CD8-positive, alpha-beta T cell number ( J:110416 )

• mice have fewer single positive CD4+ and CD8+ thymocytes compared to in wild-type mice

decreased spleen weight ( J:110416 )

abnormal immunoglobulin level ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit an increase in production of immunoglobulins (IgA, IgG, and IgM) compared with similarly treated wild-type mice

adipose tissue

increased total body fat amount ( J:66077 )

• in males at 4 months of age but not at 1 or 2 months of age

increased gonadal fat pad weight ( J:66077 )

• in males at 4 months of age

increased retroperitoneal fat pad weight ( J:66077 )

• in males at 4 months of age

hematopoietic system

thymus hypoplasia ( J:110416 )

abnormal class switch recombination ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit immunoglobulin switching unlike similarly treated wild-type mice

increased double-positive T cell number ( J:110416 )

• mice have increased double positive CD4+CD8+ thymocytes compared to in wild-type mice

abnormal bone marrow cell number ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit a decrease in bone marrow cellularity unlike similarly treated wild-type mice

abnormal B cell number ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit a reduced decrease in the frequency of B cells (including pre-B cells, pro-B cells, and newly formed B cells) compared with similarly treated wild-type mice

decreased CD4-positive, alpha-beta T cell number ( J:110416 )

• mice have fewer single positive CD4+ and CD8+ thymocytes compared to in wild-type mice

decreased CD8-positive, alpha-beta T cell number ( J:110416 )

• mice have fewer single positive CD4+ and CD8+ thymocytes compared to in wild-type mice

decreased spleen weight ( J:110416 )

abnormal immunoglobulin level ( J:82423 )

• 17beta-estradiol-treated castrated mice fail to exhibit an increase in production of immunoglobulins (IgA, IgG, and IgM) compared with similarly treated wild-type mice

endocrine/exocrine glands

thymus hypoplasia ( J:110416 )