Phenotypes associated with this allele

• Allele Symbol: Ar^tm1Verh
• Allele Name: targeted mutation 1, Guido Verhoeven
• Allele ID: MGI:3034098
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Ar^tm1Verh/Y Pten^tm1Hwu/Pten^tm1Hwu Tg(Pbsn-cre)4Prb/0	involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * C57BL/6 * DBA/2	MGI:5009703
cn2	Ar^tm1Verh/Y Plekha5^Tg(AMH-cre)1Flor/Plekha5^+	involves: 129S1/Sv * 129X1/SvJ * Black Swiss * C57BL/6	MGI:3036125
cn3	Ar^tm1Verh/Y Tg(Fabp4-cre)1Rev/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5502687
cn4	Ar^tm1Verh/Y Rnase10^tm1(cre)Hht/Rnase10^+	involves: 129S7/SvEvBrd * C57BL/6	MGI:5051914
ot5	Ar^tm1Verh/Y	involves: 129S1/Sv * 129X1/SvJ	MGI:3036137

Genotype
MGI:5009703

cn1

• Allelic Composition: Ar^tm1Verh/Y; Pten^tm1Hwu/Pten^tm1Hwu; Tg(Pbsn-cre)4Prb/0
• Genetic Background: involves: 129S1/Sv * 129S4/SvJae * 129X1/SvJ * C57BL/6 * DBA/2

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

neoplasm

increased prostate gland adenocarcinoma incidence ( J:172730 )

♂ • mutants develop adenocarcinoma in the dorsolateral lobes of the prostate

♂ • cancer progression is similar to single conditional Pten mice

♂ • proliferation and apoptotic indexes are increased in the cancers, most notably in the proximal regions of the dorsal-lateral lobe

♂ • mutant tumors contain low or no p63+ cells, similar to human prostate cancer

♂ • castrated mutants develop cancer outgrowths in the dorsolateral lobes, indicating that mutants develop castrate-resistant prostate cancer

♂ • castrated mice treated with rapamycin show a reduction in prostate volume and reduced prostate proliferation

reproductive system

increased prostate gland adenocarcinoma incidence ( J:172730 )

♂ • mutants develop adenocarcinoma in the dorsolateral lobes of the prostate

♂ • cancer progression is similar to single conditional Pten mice

♂ • proliferation and apoptotic indexes are increased in the cancers, most notably in the proximal regions of the dorsal-lateral lobe

♂ • mutant tumors contain low or no p63+ cells, similar to human prostate cancer

♂ • castrated mutants develop cancer outgrowths in the dorsolateral lobes, indicating that mutants develop castrate-resistant prostate cancer

♂ • castrated mice treated with rapamycin show a reduction in prostate volume and reduced prostate proliferation

endocrine/exocrine glands

increased prostate gland adenocarcinoma incidence ( J:172730 )

♂ • mutants develop adenocarcinoma in the dorsolateral lobes of the prostate

♂ • cancer progression is similar to single conditional Pten mice

♂ • proliferation and apoptotic indexes are increased in the cancers, most notably in the proximal regions of the dorsal-lateral lobe

♂ • mutant tumors contain low or no p63+ cells, similar to human prostate cancer

♂ • castrated mutants develop cancer outgrowths in the dorsolateral lobes, indicating that mutants develop castrate-resistant prostate cancer

♂ • castrated mice treated with rapamycin show a reduction in prostate volume and reduced prostate proliferation

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
prostate cancer		DOID:10283	OMIM:176807 OMIM:300147 OMIM:300704 OMIM:601518 OMIM:602759 OMIM:608656 OMIM:608658 OMIM:609299 OMIM:609558 OMIM:610321 OMIM:610997 OMIM:611100 OMIM:611868 OMIM:611928 OMIM:611955 OMIM:611958 OMIM:611959	J:172730

Genotype
MGI:3036125

cn2

• Allelic Composition: Ar^tm1Verh/Y; Plekha5^{Tg(AMH-cre)1Flor}/Plekha5⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * Black Swiss * C57BL/6

reproductive system

abnormal spermatid morphology ( J:88169 )

♂ • at P50, numbers of round spermatids were reduced to only 3% of wild-type numbers

♂ • the few round spermatids that formed appeared abnormal and failed to survive beyond stages VII-VIII

♂ • no elongated spermatids were detected

abnormal spermatocyte morphology ( J:88169 )

♂ • at P50, numbers of diplotene and secondary spermatocytes were reduced to 64% of wild-type numbers

decreased male germ cell number ( J:88169 )

♂ • reduced germ cell numbers associated with increased apoptosis

azoospermia ( J:88169 )

♂ • absence of elongated spermatids

increased male germ cell apoptosis ( J:88169 )

♂ • at P50, reduced male germ cell numbers were associated with a 4-5-fold increase in germ cell apoptosis

small seminiferous tubules ( J:88169 )

♂ • significant reduction in seminiferous tubule diameter at P50

♂ • however, numbers of Sertoli cells remained essentially normal based on measurement of nuclear volume per testis

abnormal Leydig cell morphology ( J:100799 )

♂ • as expected, Leydig cell cytoplasmic volume was relatively constant up to P20 and more than doubled between P20 and P50; however, an additional 32% increase occurred between P50 and P140, such that at P140 cytoplasmic volume was 23% higher than that in controls

♂ • at P50, the volumes of mitochondria and lipid droplets were 2-fold higher than in controls; however, only the increase in lipid droplets was statistically significant

decreased Leydig cell number ( J:100799 )

♂ • although Leydig cell number was normal at P12, it was reduced by >40% at later ages (P20, P50, and P140)

♂ • notably, the temporal pattern of change in LC number was generally similar to that of controls

♂ • at P50 and P140, LC number was significantly higher than in Ar^tm1.1Verh males

♂ • immunohistochemistry and quantitative PCR for LC-specific markers revealed that steroidogenic function per LC was probably increased

small testis ( J:88169 )

♂ • testes were properly descended but small in size

♂ • normal development of epididymis, vas deferens, coagulating gland, seminal gland, and prostate gland

♂ • normal development of Leydig cells and peritubular myoid cells

decreased testis weight ( J:88169 , J:100799 )

♂ • at P50, testis weight was reduced to 28.4% of wild-type weight (J:88169)

♂ • although normal at P12, testis weight was reduced to 53% of control value at P20 and to 25-30% of control value at P50 and P140 (J:100799)

arrest of spermatogenesis ( J:88169 )

♂ • spermatogenic arrest at the late spermatocyte/spermatid stage

arrest of male meiosis ( J:88169 )

♂ • normal entry into meiosis, but progressive loss of pachytene primary spermatocytes between stages VI and XII

decreased epididymis weight ( J:88169 )

♂ • at P50, epididymis weight was reduced by 30% relative to wild-type

homeostasis/metabolism

increased circulating follicle stimulating hormone level ( J:88169 )

♂ • at P50, serum FSH leves were elevated by 34% relative to wild-type

♂ • in contrast, serum levels of testosterone and luteinizing hormone remained normal

endocrine/exocrine glands

small seminiferous tubules ( J:88169 )

♂ • significant reduction in seminiferous tubule diameter at P50

♂ • however, numbers of Sertoli cells remained essentially normal based on measurement of nuclear volume per testis

abnormal Leydig cell morphology ( J:100799 )

♂ • as expected, Leydig cell cytoplasmic volume was relatively constant up to P20 and more than doubled between P20 and P50; however, an additional 32% increase occurred between P50 and P140, such that at P140 cytoplasmic volume was 23% higher than that in controls

♂ • at P50, the volumes of mitochondria and lipid droplets were 2-fold higher than in controls; however, only the increase in lipid droplets was statistically significant

decreased Leydig cell number ( J:100799 )

♂ • although Leydig cell number was normal at P12, it was reduced by >40% at later ages (P20, P50, and P140)

♂ • notably, the temporal pattern of change in LC number was generally similar to that of controls

♂ • at P50 and P140, LC number was significantly higher than in Ar^tm1.1Verh males

♂ • immunohistochemistry and quantitative PCR for LC-specific markers revealed that steroidogenic function per LC was probably increased

small testis ( J:88169 )

♂ • testes were properly descended but small in size

♂ • normal development of epididymis, vas deferens, coagulating gland, seminal gland, and prostate gland

♂ • normal development of Leydig cells and peritubular myoid cells

decreased testis weight ( J:88169 , J:100799 )

♂ • at P50, testis weight was reduced to 28.4% of wild-type weight (J:88169)

♂ • although normal at P12, testis weight was reduced to 53% of control value at P20 and to 25-30% of control value at P50 and P140 (J:100799)

growth/size/body

growth/size/body region phenotype ( J:88169 )

♂N • growth curves of hemizygous mutant males were similar to those of wild-type males

cellular

abnormal spermatid morphology ( J:88169 )

♂ • at P50, numbers of round spermatids were reduced to only 3% of wild-type numbers

♂ • the few round spermatids that formed appeared abnormal and failed to survive beyond stages VII-VIII

♂ • no elongated spermatids were detected

abnormal spermatocyte morphology ( J:88169 )

♂ • at P50, numbers of diplotene and secondary spermatocytes were reduced to 64% of wild-type numbers

decreased male germ cell number ( J:88169 )

♂ • reduced germ cell numbers associated with increased apoptosis

azoospermia ( J:88169 )

♂ • absence of elongated spermatids

arrest of male meiosis ( J:88169 )

♂ • normal entry into meiosis, but progressive loss of pachytene primary spermatocytes between stages VI and XII

increased male germ cell apoptosis ( J:88169 )

♂ • at P50, reduced male germ cell numbers were associated with a 4-5-fold increase in germ cell apoptosis

Genotype
MGI:5502687

cn3

• Allelic Composition: Ar^tm1Verh/Y; Tg(Fabp4-cre)1Rev/0
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6

adipose tissue

abnormal adipose tissue amount ( J:196857 )

♂ • while males on a normal chow diet are not obese, they show reduced perigonadal fat weight but increased interscapular brown adipose tissue at 3 months age

♂ • however, body fat composition is no longer different by 6 months of age

♂ • on a high-fat diet, males gain equal weight compared with controls, however after 24 weeks, they have more visceral fat, with increases in omental and mesenteric fat pad weights

increased brown adipose tissue amount ( J:196857 )

♂ • on a normal chow diet, males have an increase in interscapular brown adipose tissue at 3 months of age

♂ • however, white adipose tissue morphology in the perigonadal and subcutaneous depots are normal

decreased gonadal fat pad weight ( J:196857 )

♂ • on a normal chow diet, males have reduced perigonadal fat weight and proportion

increased mesenteric fat pad weight ( J:196857 )

♂ • after 24 weeks of a high-fat diet, males show an increase in mesenteric fat pad weight compared to controls

increased omental fat pad weight ( J:196857 )

♂ • after 24 weeks of a high-fat diet, males show an increase in omental fat pad weight compared to controls

increased interscapular fat pad weight ( J:196857 )

♂ • on a normal chow diet, males have an increase in interscapular brown adipose tissue at 3 months of age

growth/size/body

decreased susceptibility to weight gain ( J:196857 )

♂ • on a normal chow diet, males gain less weight than controls at 3 months of age

homeostasis/metabolism

hyperglycemia ( J:196857 )

♂ • males are euglycemic at 3 months of age, however between 3 and 12 months of age, males are unable to sustain the normal increase in insulin secretory capacity, and they develop hyperglycemia

♂ • after 24 weeks on a high-fat diet, mutants have a poorer secretory response and become more hyperglycemic than controls

increased circulating insulin level ( J:196857 )

♂ • males are euglycemic but hyperinsulinemic both in the fasted state and during glucose tolerance testing at 3 months of age

increased circulating triglyceride level ( J:196857 )

♂ • 3 month old males have elevated plasma triglyceride levels but normal liver triglycerides

impaired glucose tolerance ( J:196857 )

♂ • males show age-related glucose intolerance

insulin resistance ( J:196857 )

♂ • insulin resistance in 3 month old males on a normal diet, as indicated by hyperinsulinemia both in the fasted state and during glucose tolerance

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:196857

Genotype
MGI:5051914

cn4

• Allelic Composition: Ar^tm1Verh/Y; Rnase10^tm1(cre)Hht/Rnase10⁺
• Genetic Background: involves: 129S7/SvEvBrd * C57BL/6

reproductive system

abnormal male genitalia morphology ( J:173897 )

♂

abnormal testis morphology ( J:173897 )

♂

seminiferous tubule degeneration ( J:173897 )

♂ • undergoing degeneration at 4 months

♂ • germinal epithelium lost in many tubules

♂ • intraepithelial cysts frequently found

enlarged testis ( J:173897 )

♂ • at four months

♂ • as a result of fluid retention

testicular atrophy ( J:173897 )

♂

abnormal epididymis morphology ( J:173897 )

♂ • spermatic granulomata frequently obstruct the epididymes

abnormal caput epididymis morphology ( J:173897 )

♂ • initial segment hypoplasia by 30 days

♂ • epididymis becomes obstructed at the level of the caput

♂ • sperm build-up starting around 40 days causes severe dilation and finally, complete occlusion

abnormal epididymis epithelium morphology ( J:173897 )

♂ • decreased height after 20-25 days in segments I and II

epididymis epithelium degeneration ( J:173897 )

♂ • begins to degenerate distal to occlusion

abnormal male reproductive system physiology ( J:173897 )

♂

testis inflammation ( J:173897 )

♂ • some males develop unilateral orchitis

male infertility ( J:173897 )

♂ • no pregnancies after mating to CD1 females

♂ • vaginal plugs are produced

endocrine/exocrine glands

abnormal testis morphology ( J:173897 )

♂

seminiferous tubule degeneration ( J:173897 )

♂ • undergoing degeneration at 4 months

♂ • germinal epithelium lost in many tubules

♂ • intraepithelial cysts frequently found

enlarged testis ( J:173897 )

♂ • at four months

♂ • as a result of fluid retention

testicular atrophy ( J:173897 )

♂

testis inflammation ( J:173897 )

♂ • some males develop unilateral orchitis

immune system

testis inflammation ( J:173897 )

♂ • some males develop unilateral orchitis

Genotype
MGI:3036137

ot5

• Allelic Composition: Ar^tm1Verh/Y
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

reproductive system

reproductive system phenotype ( J:88169 )

♂N • genotypic males had a male phenotype and showed normal development of the male urogenital system