Dicer1<tm1Bdh> Targeted Allele Detail MGI Mouse (MGI:3589208)

Dicer1^tm1Bdh
Targeted Allele Detail

Nomenclature

Symbol:	Dicer1^tm1Bdh
Name:	Dicer1, Dcr-1 homolog (Drosophila); targeted mutation 1, Brian D Harfe
MGI ID:	MGI:3589208
Synonyms:	Dcr^flox, Dicer^flox, Dicer1^fl
Gene:	Dicer1 Location: Chr12:105925952-105990162 bp, - strand Genetic Position: Chr12, 51.0 cM, cytoband E-F1

Mutation
origin

Germline Transmission:	Earliest citation of germline transmission: J:100475
Parent Cell Line:	Not Specified (ES Cell)
Strain of Origin:	Not Specified

Mutation
description

Allele Type:	Targeted (Floxed/Frt)
Mutation:	Insertion
	A targeting vector was designed to insert loxP sites around the exon that encodes most of the second RNaseIII domain as well as an frt-flanked neo within the loxP-encompassed sequence. Cre-mediated removal of the sequence would result in the loss of 90 amino acids, a loss that does not create a downstream frame-shift or an unstable protein. (J:100475)

Find Mice (IMSR)

Mouse strains and cell lines available from the International Mouse Strain Resource (IMSR)

Carrying this Mutation:	Mouse Strains: 2 strains available Cell Lines: 0 lines available
Carrying any Dicer1 Mutation:	9 strains or lines available

Phenotype
summary

Phenotype Summary by Mammalian Phenotype terms

(show or hide all annotated terms)

Genotypes are listed in the next section.

Key:

hm	homozygous	ht	heterozygous
cn	conditional genotype	cx	complex: > 1 genome feature
tg	involves transgenes	ot	other: hemizygous, indeterminate,...
N	normal phenotype		expected model not found

Affected Systems	Genotypes:	cn1	cn2	cn3	cn4	cn5	cn6	cn7
behavior/neurological							√
abnormal behavior							√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
cardiovascular system			√	√
vascular inflammation			√	√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
embryogenesis								√
failure of embryo implantation								√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
endocrine/exocrine glands		√						√
Leydig cell hyperplasia		√
abnormal Sertoli cell morphology		√
ectopic Sertoli cells		√
abnormal seminiferous epithelium morphology		√
small seminiferous tubules		√
seminiferous tubule degeneration		√
small testis		√
decreased testis weight		√
testicular atrophy		√
decreased ovary weight								√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
growth/size							√
weight loss							√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
hematopoietic system			√	√	√		√
enlarged spleen			√	√			√
abnormal effector T cell morphology							√
abnormal regulatory T cell morphology							√
decreased regulatory T cell number					√		√
abnormal splenic cell ratio							√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
homeostasis/metabolism								√
homeostasis/metabolism phenotype								N
decreased circulating progesterone level								√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
immune system			√	√	√		√
vascular inflammation			√	√
enlarged spleen			√	√			√
enlarged lymph nodes			√	√			√
liver inflammation			√	√			√
lung inflammation			√	√			√
abnormal effector T cell morphology							√
abnormal regulatory T cell morphology							√
decreased regulatory T cell number					√		√
abnormal splenic cell ratio							√
abnormal lymph node cell ratio							√
abnormal CD4-positive T cell physiology							√
abnormal regulatory T cell physiology							√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
life span/aging			√	√			√
premature death			√	√			√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
limbs/digits/tail						√
abnormal forelimb morphology						√
abnormal hindlimb morphology						√
oligodactyly						√
abnormal long bone morphology						√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
liver/biliary system			√	√			√
liver inflammation			√	√			√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
reproductive system		√						√
reproductive system phenotype		N						N
Leydig cell hyperplasia		√
abnormal Sertoli cell morphology		√
ectopic Sertoli cells		√
abnormal seminiferous epithelium morphology		√
small seminiferous tubules		√
seminiferous tubule degeneration		√
small testis		√
decreased testis weight		√
testicular atrophy		√
abnormal male germ cell morphology		√
abnormal spermatid morphology		√
decreased male germ cell number		√
azoospermia		√
male germ cell apoptosis		√
abnormal spermatogenesis		√
male infertility		√
decreased ovary weight								√
abnormal oviduct morphology								√
short oviduct								√
abnormal uterus morphology								√
decreased endometrial gland number								√
thin myometrium								√
short uterine horn								√
small uterus								√
decreased uterus weight								√
abnormal oviduct transport								√
abnormal superovulation								√
decreased ovulation frequency								√
abnormal pregnancy								√
failure of embryo implantation								√
female infertility								√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
respiratory system			√	√			√
lung inflammation			√	√			√
		cn1	cn2	cn3	cn4	cn5	cn6	cn7
skeleton						√	√
abnormal long bone morphology						√
delayed endochondral bone ossification						√
kyphosis							√

Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype	Allelic Composition	Genetic Background
cn1	Dicer1^tm1Bdh/Dicer1^tm1Bdh Tg(AMH-cre)1Flor/0	involves: 129/Sv * C57BL/6J
reproductive system reproductive system phenotype (J:145178) adult males show no differences in mounting and copulatory activity or in testicular descent and masculinization of internal reproductive organs (seminal vesicles and prostate) relative to control littermates Leydig cell hyperplasia (J:145178) Leydig cell hyperplasia is already noted at P5, persists throughout adulthood, and becomes massive by 6 months of age however, no significant differences in testicular testosterone levels are observed from P0 to P60 abnormal Sertoli cell morphology (J:145178) as early as P5, mutant males display Sertoli cell nuclear mislocalization with almost complete absence of lumen at P15, mutant Sertoli cell nuclei display an abnormal circular rather than flattened triangular shape a 1.25-, 1.5-, and 2.6-fold increase in Sertoli cell proliferation is observed at P0, P5, and P15, respectively, suggesting delayed Sertoli cell maturation significant Sertoli cell apoptosis is noted at P5; however, by P21, apoptotic cells are almost exclusively germ cells by 3 months of age, obvious defects in Sertoli cell cyto-architecture and polarity are observed ectopic Sertoli cells (J:145178) as early as P5, mutant Sertoli cell nuclei are mislocalized in the center of seminiferous tubes instead of the periphery abnormal seminiferous epithelium morphology (J:145178) at P60, the mutant seminiferous epithelium appears disorganized small seminiferous tubules (J:145178) at P60, mutant seminiferous tubules are reduced in diameter and devoid of lumen seminiferous tubule degeneration (J:145178) as early as P5, numerous pycnotic cells are detected within mutant tubes at P42, almost all mutant tubes have become severely vacuolized; however, a few less severely affected tubes display a lumen by 3 months of age, most seminiferous tubules have degenerated into Sertoli-cell-only tubes with a severely impaired Sertoli cell morphology small testis (J:145178) at P15 and P60, mutant testes show a 80% and 90% reduction in size, respectively, relative to control testes by 6 months of age, mutant testis size is only 5% of that in control littermates decreased testis weight (J:145178) at P60, mutant males show a 90% reduction in testis weight relative to control littermates testicular atrophy (J:145178) severe testicular degeneration is noted at P60 and worsens upon aging by 6 months of age, mutant testes have degenerated into a mass of interstitial cells containing rare remaining tubes abnormal male germ cell morphology (J:145178) at P60, numerous exfoliated germ cells are detected in the lumen of mutant epididymal ducts decreased male germ cell number (J:145178) at P60, mutant male germ cells are severely disorganized and reduced in number by 6 months of age, the few remaining tubes are almost completely devoid of germ cells azoospermia (J:145178) at P60, mutant males show complete absence of mature spermatozoa in testes and epididymal ducts male germ cell apoptosis (J:145178) significant male germ cell apoptosis is noted at P15 and P21 by P42, mutant male germ cells exhibit extensive apoptosis abnormal spermatogenesis (J:145178) at P60, mutant males show severe spermatogenic defects including vacuolization, Sertoli-cell-only tubes, tubes with spermatogenic arrest at an early post-meiotic stage, and disorganization of the seminiferous epithelium abnormal spermatid morphology (J:145178) at P42, round spermatids are severely reduced in number while elongated spermatids are entirely absent in mutant testes male infertility (J:145178) mutant males fail to produce any offspring during a 6-month mating period with wild-type C57BL/6J females endocrine/exocrine glands Leydig cell hyperplasia (J:145178) Leydig cell hyperplasia is already noted at P5, persists throughout adulthood, and becomes massive by 6 months of age however, no significant differences in testicular testosterone levels are observed from P0 to P60 abnormal Sertoli cell morphology (J:145178) as early as P5, mutant males display Sertoli cell nuclear mislocalization with almost complete absence of lumen at P15, mutant Sertoli cell nuclei display an abnormal circular rather than flattened triangular shape a 1.25-, 1.5-, and 2.6-fold increase in Sertoli cell proliferation is observed at P0, P5, and P15, respectively, suggesting delayed Sertoli cell maturation significant Sertoli cell apoptosis is noted at P5; however, by P21, apoptotic cells are almost exclusively germ cells by 3 months of age, obvious defects in Sertoli cell cyto-architecture and polarity are observed ectopic Sertoli cells (J:145178) as early as P5, mutant Sertoli cell nuclei are mislocalized in the center of seminiferous tubes instead of the periphery abnormal seminiferous epithelium morphology (J:145178) at P60, the mutant seminiferous epithelium appears disorganized small seminiferous tubules (J:145178) at P60, mutant seminiferous tubules are reduced in diameter and devoid of lumen seminiferous tubule degeneration (J:145178) as early as P5, numerous pycnotic cells are detected within mutant tubes at P42, almost all mutant tubes have become severely vacuolized; however, a few less severely affected tubes display a lumen by 3 months of age, most seminiferous tubules have degenerated into Sertoli-cell-only tubes with a severely impaired Sertoli cell morphology small testis (J:145178) at P15 and P60, mutant testes show a 80% and 90% reduction in size, respectively, relative to control testes by 6 months of age, mutant testis size is only 5% of that in control littermates decreased testis weight (J:145178) at P60, mutant males show a 90% reduction in testis weight relative to control littermates testicular atrophy (J:145178) severe testicular degeneration is noted at P60 and worsens upon aging by 6 months of age, mutant testes have degenerated into a mass of interstitial cells containing rare remaining tubes
Genotype	Allelic Composition	Genetic Background
cn2	Dicer1^tm1Bdh/Dicer1^tm1Bdh Foxp3^{tm4(YFP/cre)Ayr}/Y	involves: 129S1/Sv * 129X1/SvJ
life span/aging premature death (J:138683) females become ill at 2-3 weeks, exhibiting 100% mortality at <25 days immune system vascular inflammation (J:138683) cuffing around blood vessels by inflammatory cells in pancreas, kidney and skeletal muscle is observed enlarged spleen (J:138683) enlarged lymph nodes (J:138683) liver inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice lung inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice hematopoietic system enlarged spleen (J:138683) cardiovascular system vascular inflammation (J:138683) cuffing around blood vessels by inflammatory cells in pancreas, kidney and skeletal muscle is observed liver/biliary system liver inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice respiratory system lung inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice
Genotype	Allelic Composition	Genetic Background
cn3	Dicer1^tm1Bdh/Dicer1^tm1Bdh Foxp3^{tm4(YFP/cre)Ayr}/Foxp3^{tm4(YFP/cre)Ayr}	involves: 129S1/Sv * 129X1/SvJ
life span/aging premature death (J:138683) males become ill at 2-3 weeks, exhibiting 100% mortality at <25 days immune system vascular inflammation (J:138683) cuffing around blood vessels by inflammatory cells in pancreas, kidney and skeletal muscle is observed enlarged spleen (J:138683) enlarged lymph nodes (J:138683) liver inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice lung inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice hematopoietic system enlarged spleen (J:138683) cardiovascular system vascular inflammation (J:138683) cuffing around blood vessels by inflammatory cells in pancreas, kidney and skeletal muscle is observed liver/biliary system liver inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice respiratory system lung inflammation (J:138683) large areas are infiltrated by inflammatory cells in moribund mice
Genotype	Allelic Composition	Genetic Background
cn4	Dicer1^tm1Bdh/Dicer1^tm1Bdh Tg(CD4-cre)1Cwi/0	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2
hematopoietic system decreased regulatory T cell number (J:138683) mature peripheral T reg cells are reduced in frequency immune system decreased regulatory T cell number (J:138683) mature peripheral T reg cells are reduced in frequency
Genotype	Allelic Composition	Genetic Background
cn5	Dicer1^tm1Bdh/Dicer1^tm1Bdh Tg(Prrx1-cre)1Cjt/0	involves: C57BL/6J * SJL/J
limbs/digits/tail abnormal forelimb morphology (J:100475) at E11 the forelimbs are smaller and at E12.5 the forelimb size resembles that of wild-type forelimbs at E11.5 starting at E10.5 increased cell death is seen in the limb mesoderm abnormal hindlimb morphology (J:100475) the hindlimbs are smaller but not as severely affected as the forelimbs starting at E12.5 increased cell death is seen in the limb mesoderm oligodactyly (J:100475) forelimbs show loss of digits and some fusion of digits abnormal long bone morphology (J:100475) the long bones of the arms and legs appear twisted skeleton abnormal long bone morphology (J:100475) the long bones of the arms and legs appear twisted delayed endochondral bone ossification (J:100475) bone formation from cartilage is delayed in the long bones of the limbs
Genotype	Allelic Composition	Genetic Background
cn6	Dicer1^tm1Bdh/Dicer1^tm1Bdh Tg(Foxp3-EGFP/cre)1Jbs/0	involves: NOD/ShiLt
life span/aging premature death (J:138808) all mice die by 6-8 weeks of age growth/size weight loss (J:138808) aging animals display weight loss behavior/neurological abnormal behavior (J:138808) aging animals display reduced mobility immune system abnormal effector T cell morphology (J:138808) number of CTLA4-expressing CD4+ Foxp3- effector T cells increase to >50% of splenic and >70% of lymph node CD4+ T cells compared to <10% in wild-type littermates abnormal regulatory T cell morphology (J:138808) T reg cells have a higher percentage of CD103+ T cells and greater number of CD62^lo cells decreased regulatory T cell number (J:138808) percentage of regulatory T (T reg) cells in spleen and peripheral blood is reduced to 33% of controls enlarged spleen (J:138808) observed in all aging animals (>5 weeks of age) abnormal splenic cell ratio (J:138808) dramatic increase in splenic T cells is seen in 4-6 week old mice relative to controls abnormal lymph node cell ratio (J:138808) dramatic increase in lymph node T cells is seen in 4-6 week old mice; however percentage of regulatory T cells is maintained enlarged lymph nodes (J:138808) observed in all aging animals (>5 weeks of age) abnormal CD4-positive T cell physiology (J:138808) many effector T cells have high levels of Il4, Il10 and interferon gamma, Ifng whereas <1% of cells from wild-type express Il4, Il10, Il17 or Ifng abnormal regulatory T cell physiology (J:138808) CD4+ Foxp3+ T regs have a more prominent activated phenotype (increased expression of CD25, CTLA4 and glucocorticoid-induced TNFR) liver inflammation (J:138808) tissue displays extensive mononuclear cell infiltration lung inflammation (J:138808) tissue displays extensive mononuclear cell infiltration tissue has dense predominantly peribronchovascular infiltrates, composed of CD4+ and Cd8+ T cells hematopoietic system abnormal effector T cell morphology (J:138808) number of CTLA4-expressing CD4+ Foxp3- effector T cells increase to >50% of splenic and >70% of lymph node CD4+ T cells compared to <10% in wild-type littermates abnormal regulatory T cell morphology (J:138808) T reg cells have a higher percentage of CD103+ T cells and greater number of CD62^lo cells decreased regulatory T cell number (J:138808) percentage of regulatory T (T reg) cells in spleen and peripheral blood is reduced to 33% of controls enlarged spleen (J:138808) observed in all aging animals (>5 weeks of age) abnormal splenic cell ratio (J:138808) dramatic increase in splenic T cells is seen in 4-6 week old mice relative to controls liver/biliary system liver inflammation (J:138808) tissue displays extensive mononuclear cell infiltration respiratory system lung inflammation (J:138808) tissue displays extensive mononuclear cell infiltration tissue has dense predominantly peribronchovascular infiltrates, composed of CD4+ and Cd8+ T cells skeleton kyphosis (J:138808) seen in aging animals
Genotype	Allelic Composition	Genetic Background
cn7	Amhr2^tm3(cre)Bhr/Amhr2⁺ Dicer1^tm1Bdh/Dicer1^tm1Bdh	Not Specified
reproductive system reproductive system phenotype (J:142113) mutant females display normal estrous cycles and mating behavior relative to control littermates decreased ovary weight (J:142113) adult day-1 pregnant female mutants display reduced ovarian weights relative to age-matched control littermates abnormal oviduct morphology (J:142113) unlike wild-type, mutant oviducts lack extensive coiling and appear more transparent under a dissecting microscope distended sac-like structures filled with clear fluid are observed at the end of the oviduct near the uterotubal junction oviducts of both immature and pregnant female mutants rupture easily, do not appear patent, and cannot be flushed mutant oviducts display a disorganized epithelial cell layer while the isthmus region is almost devoid of smooth muscle tissue short oviduct (J:142113) both untreated and eCG+hCG-treated immature (day 25) and adult day-1 pregnant female mutants display shorter oviducts that are less than one half the length of control littermates abnormal uterus morphology (J:142113) mutant uteri appear more transparent than control uteri under a dissecting microscope decreased endometrial gland number (J:142113) both eCG+hCG-treated immature and adult pregnant female mutants exhibit reduced numbers of uterine glands relative to control littermates thin myometrium (J:142113) both eCG+hCG-treated immature and adult pregnant female mutants display a thinner myometrial layer relative to control littermates short uterine horn (J:142113) both untreated and eCG+hCG-treated immature (day 25) female mutants show a significant reduction in the length and diameter of uterine horns relative to control littermates small uterus (J:142113) mutant uteri are hypotrophic, approximately two thirds the length of control littermates, and contain much less smooth muscle decreased uterus weight (J:142113) adult day-1 pregnant female mutants display reduced uterine weights relative to age-matched control littermates abnormal oviduct transport (J:142113) unlike embryos developing in wild-type females, embryos in mutant females fail to enter the uterus on day 4 of pregnancy, indicating disruption of oviductal transport; most are found in the upper one third of the oviduct instead of the uterus only a few embryos progress through the oviduct to the isthmus; however, these are mostly fragmented and some zonae pellucidae are lost in contrast, in vitro cultured pronuclear (day-1) embryos collected from mutant donors develop at a similar rate as those derived from wild-type females abnormal superovulation (J:142113) immature eCG+hCG-treated female mutants display a reduced ovulation rate relative to similarly treated wild-type females immature mutant females given eCG alone (46 hrs) exhibit fewer large antral follicles in their ovaries than similarly treated control littermates decreased ovulation frequency (J:142113) female mutants exhibit decreased numbers of naturally ovulated cumulus-oocyte complexes relative to control littermates abnormal pregnancy (J:142113) embryos collected from mutant females on day-3 of pregnancy appear developmentally delayed relative to control embryos embryos collected from mutant females on day-4 of pregnancy exhibit increased fragmentation and degeneration relative to control embryos however, in vitro fertilized oocytes derived from mutant donor mice are able to establish a pregnancy in wild-type recipients with normal fetal development up to at least E15 failure of embryo implantation (J:142113) at day-6 and -7 of pregnancy, mutant females exhibit no evidence of implantation; in contrast, all wild-type females display 9.8 � 0.4 implantation sites per dam female infertility (J:142113) mutant females fail to produce any offspring over a 5-month breeding period with adult wild-type males of known fertility in contrast, male mutants are able to sire multiple litters with wild-type females homeostasis/metabolism homeostasis/metabolism phenotype (J:142113) eCG+hCG-treated immature female mutants show no significant changes in estrogen levels relative to control littermates decreased circulating progesterone level (J:142113) on day-6 of pregnancy, mutant females show a slight (24%) decrease in serum progesterone levels relative to controls however, no significant changes in serum progesterone concentrations are noted through day-4 of pregnancy embryogenesis failure of embryo implantation (J:142113) at day-6 and -7 of pregnancy, mutant females exhibit no evidence of implantation; in contrast, all wild-type females display 9.8 � 0.4 implantation sites per dam endocrine/exocrine glands decreased ovary weight (J:142113) adult day-1 pregnant female mutants display reduced ovarian weights relative to age-matched control littermates

References

Original:	J:100475 Harfe BD et al., "The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb." Proc Natl Acad Sci U S A 2005 Aug 2;102(31):10898-903
All:	23 reference(s)

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