Phenotypes associated with this allele

• Allele Symbol: Rbl2^tm1Tyj
• Allele Name: targeted mutation 1, Tyler Jacks
• Allele ID: MGI:1857449
• Summary: 8 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Rbl2^tm1Tyj/Rbl2^tm1Tyj	involves: 129S2/SvPas * C57BL/6	MGI:3582619
ht2	Rbl2^tm1Tyj/Rbl2^+	involves: 129S2/SvPas * C57BL/6	MGI:3582620
cn3	Rb1^tm2Brn/Rb1^tm2Brn Rbl2^tm1Tyj/Rbl2^tm1Tyj Tg(Myh6-cre)2182Mds/Tg(Myh6-cre)2182Mds	involves: 129 * 129S2/SvPas * FVB/N	MGI:3710679
cn4	Rb1^tm3Tyj/Rb1^tm3Tyj Rbl2^tm1Tyj/Rbl2^tm1Tyj Tg(Nes-cre)1Atp/0	involves: 129S2/SvPas * 129S4/SvJae * FVB/N	MGI:3783528
cx5	Rbl1^tm1Tyj/Rbl1^tm1Tyj Rbl2^tm1Tyj/Rbl2^+	involves: 129S2/SvPas * C57BL/6	MGI:3582650
cx6	Rbl1^tm1Tyj/Rbl1^tm1Tyj Rbl2^tm1Tyj/Rbl2^tm1Tyj	involves: 129S2/SvPas * C57BL/6	MGI:3582621
cx7	Rbl1^tm1Tyj/Rbl1^+ Rbl2^tm1Tyj/Rbl2^tm1Tyj	involves: 129S2/SvPas * C57BL/6	MGI:3582649
cx8	Rbl1^tm1.1Fad/Rbl1^tm1.1Fad Rbl2^tm1Tyj/Rbl2^tm1Tyj	involves: 129S2/SvPas * C57BL/6 * FVB/N	MGI:5614114

Genotype
MGI:3582619

hm1

• Allelic Composition: Rbl2^tm1Tyj/Rbl2^tm1Tyj
• Genetic Background: involves: 129S2/SvPas * C57BL/6

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

normal phenotype

no abnormal phenotype detected ( J:34725 )

• homozygotes are viable and fertile, and display no detectable histologic abnormalities at birth or at 2 months of age

cellular

cellular phenotype ( J:34725 )

N • surprisingly, mouse embryonic fibroblasts derived from homozygous mutants exhibit normal growth characteristics in culture

N • gel mobility shft analysis indicated that Rbl1 largely replaces Rbl2 as the major E2F-associated species in mutant fibroblasts

integument

integument phenotype ( J:82802 )

N • newborn homozygotes display normal epidermal terminal differentiation relative to heterozygous mutant littermates

Genotype
MGI:3582620

ht2

• Allelic Composition: Rbl2^tm1Tyj/Rbl2⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6

normal phenotype

no abnormal phenotype detected ( J:34725 )

• heterozygotes appear normal and show no increase in morbidity or mortality up to 16 months of age relative to wild-type mice

Genotype
MGI:3710679

cn3

• Allelic Composition: Rb1^tm2Brn/Rb1^tm2Brn; Rbl2^tm1Tyj/Rbl2^tm1Tyj; Tg(Myh6-cre)2182Mds/Tg(Myh6-cre)2182Mds
• Genetic Background: involves: 129 * 129S2/SvPas * FVB/N

mortality/aging

premature death ( J:97589 )

• 36% die suddenly by 12 weeks of age and only 48% survive to 6 months of age

cardiovascular system

increased myocardial fiber size ( J:97589 )

• cardiomyocytes have an increase in diameter and contain large, hyperchromatic nuclei

enlarged heart ( J:97589 )

• mutants exhibit a 3-fold increase in the heart weight-to-body weight ratio at 8 weeks of age but not in the neonatal time period

dilated heart left ventricle ( J:97589 )

• mutants surviving to 12 weeks of age show evidence of LV dilation

decreased ventricle muscle contractility ( J:97589 )

• end-diastolic diameter and end-systolic diameter are increased and left ventricular fractional shortening and circumferential shortening velocity are decreased in mutants surviving to 12 seeks of age, indicating left ventricular systolic dysfunction

decreased heart rate ( J:97589 )

• seen in mutants surviving to 12 weeks of age

abnormal myocardial fiber physiology ( J:97589 )

• hearts exhibit persistent myocyte cycling

respiratory system

respiratory distress ( J:97589 )

• 36% develop signs of respiratory distress

homeostasis/metabolism

edema ( J:97589 )

• 36% develop signs of generalized edema

muscle

increased myocardial fiber size ( J:97589 )

• cardiomyocytes have an increase in diameter and contain large, hyperchromatic nuclei

decreased ventricle muscle contractility ( J:97589 )

• end-diastolic diameter and end-systolic diameter are increased and left ventricular fractional shortening and circumferential shortening velocity are decreased in mutants surviving to 12 seeks of age, indicating left ventricular systolic dysfunction

growth/size/body

enlarged heart ( J:97589 )

• mutants exhibit a 3-fold increase in the heart weight-to-body weight ratio at 8 weeks of age but not in the neonatal time period

Genotype
MGI:3783528

cn4

• Allelic Composition: Rb1^tm3Tyj/Rb1^tm3Tyj; Rbl2^tm1Tyj/Rbl2^tm1Tyj; Tg(Nes-cre)1Atp/0
• Genetic Background: involves: 129S2/SvPas * 129S4/SvJae * FVB/N

mortality/aging

decreased tumor-free survival time ( J:91406 )

• mice with mosaic cre expression due to maternal inheritance of Tg(Nes-cre)1Mrt exhibit an average tumor-free lifespan of 97 days but where sacrificed when moribund

vision/eye

abnormal retina apoptosis ( J:91406 )

• apoptosis levels are higher than in wild-type mice but not higher than in Rb1^tm3Tyj/Rb1^tm3Tyj Tg(Nes-cre)1Mrt mice

increased retinoblastoma incidence ( J:91406 )

• mice with mosaic cre expression due to maternal inheritance of Tg(Nes-cre)1Mrt exhibit bilateral retinoblastomas that invade surrounding muscle, exhibit rosettes, have foci with high levels of apoptosis and mitoses and are of amacrine lineage

neoplasm

increased retinoblastoma incidence ( J:91406 )

• mice with mosaic cre expression due to maternal inheritance of Tg(Nes-cre)1Mrt exhibit bilateral retinoblastomas that invade surrounding muscle, exhibit rosettes, have foci with high levels of apoptosis and mitoses and are of amacrine lineage

reproductive system

transmission ratio distortion ( J:91406 )

• fewer than expected mice are produced with maternal inheritance of Tg(Nes-cre)1Mrt

cellular

abnormal retina apoptosis ( J:91406 )

• apoptosis levels are higher than in wild-type mice but not higher than in Rb1^tm3Tyj/Rb1^tm3Tyj Tg(Nes-cre)1Mrt mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
retinoblastoma		DOID:768	OMIM:180200	J:91406

Genotype
MGI:3582650

cx5

• Allelic Composition: Rbl1^tm1Tyj/Rbl1^tm1Tyj; Rbl2^tm1Tyj/Rbl2⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6

mortality/aging

postnatal lethality, incomplete penetrance ( J:34725 )

• mutants die at an increased rate during the first and second week after birth; survivors fail to reach normal adult weight

limbs/digits/tail

abnormal forelimb morphology ( J:34725 )

• at 18.0 dpc, mutant mice exhibit forelimb shortening and thickening

short limbs ( J:34725 )

• beginning at 15.0-16.0 dpc, mutants display a mild reduction in limb length

short forelimb ( J:34725 )

• at 18.0 dpc

reproductive system

delayed fertility ( J:34725 )

• surviving mutant mice display delayed fertility

reduced female fertility ( J:34725 )

♀ • surviving mutant females show reduced fertility

craniofacial

short snout ( J:34725 )

• beginning at 15.0-16.0 dpc, mutants display a mildly shortened snout

growth/size/body

short snout ( J:34725 )

• beginning at 15.0-16.0 dpc, mutants display a mildly shortened snout

decreased body weight ( J:34725 )

• mutant mice display normal weight at birth but reach only ~65% of normal weight at the age of 2-3 weeks

distended abdomen ( J:34725 )

• beginning at 15.0-16.0 dpc, mutants display a slightly distended abdomen

Genotype
MGI:3582621

cx6

• Allelic Composition: Rbl1^tm1Tyj/Rbl1^tm1Tyj; Rbl2^tm1Tyj/Rbl2^tm1Tyj
• Genetic Background: involves: 129S2/SvPas * C57BL/6

mortality/aging

neonatal lethality, complete penetrance ( J:34725 )

• generally, double mutants are born alive but die shortly after birth

perinatal lethality, incomplete penetrance ( J:34725 )

• occasionally, double mutant mice are not removed from their amniotic sacs by their mothers and either are born dead or die partly as a result of maternal rejection

skeleton

abnormal craniofacial bone morphology ( J:34725 )

interparietal bone hypoplasia ( J:34725 )

• at 19.0 dpc, the interparietal bone of double mutant mice appears underdeveloped; most other cranial bones develop normally

abnormal supraoccipital bone morphology ( J:34725 )

• at 19.0 dpc, the supraoccipital bone of double mutant mice appears slightly underdeveloped

absent incisors ( J:82802 )

• a few double mutant embryos display incisors anodontia with undifferentiated mesenchymal tissue

small incisors ( J:82802 )

• most double mutant embryos exhibit incisors microdontia

abnormal tooth development ( J:82802 )

• when present, the tooth germ of double mutant embryos shows variable degrees of microdontia along with hypoplasia and disorganization of the odontoblast layer

abnormal limb bone morphology ( J:34725 )

abnormal humerus morphology ( J:34725 )

• at 16.0 dpc, the mutant humerus shows complete lack of ossification

increased diameter of humerus ( J:34725 )

• at 19.0 dpc, double mutants show abnormal thickening of the humerus

short humerus ( J:34725 )

• at 19.0 dpc, double mutants show abnormal shortening of the humerus

short radius ( J:34725 )

• at 19.0 dpc, double mutants show abnormal shortening of the radius

increased diameter of radius ( J:34725 )

• at 19.0 dpc, double mutants show abnormal thickening of the radius

short ulna ( J:34725 )

• at 19.0 dpc, double mutants show abnormal shortening of the ulna

increased diameter of ulna ( J:34725 )

• at 19.0 dpc, double mutants show abnormal thickening of the ulna

abnormal tracheal cartilage morphology ( J:34725 )

• at 18.0 dpc, some double mutants display abnormal tracheal cartilage formation, contributing to airway dysfunction and possibly neonatal lethality

abnormal long bone epiphyseal plate morphology ( J:34725 )

• at 18 dpc, the growth plates of mutant humerus appear widened, the epiphyses are deformed and thickened, and the zone of flattened cells elongated

abnormal long bone epiphyseal plate proliferative zone ( J:34725 )

• chondrocytes in the epiphyseal centers of mutant humeri proliferate at an increased rate and reach and higher density

• chondrocytes in the zone of flattened cells exhibit a delay in the cell cycle withdrawal and hypertrophy associated with terminal differentiation

• however, chondrocytes eventually stop proliferating in mutant growth plates

increased width of hypertrophic chondrocyte zone ( J:34725 )

• in 18.0 dpc mutant humerus, hypertrophic chondrocytes fail to form well-organized columns, and ossification of cancellous bone begins at an increased distance from the articular surface

abnormal rib development ( J:34725 )

• abnormal rib development may prevent adequate lung expansion and inflation, contributing to neonatal lethality

small thoracic cage ( J:34725 )

• at 16.0 dpc, double mutants show a reduced rib cage size

abnormal chondrocyte morphology ( J:34725 )

• at 18.0 dpc, chondrocyte density in the epiphyseal centers of mutant humeri is increased by ~2-fold; at 16.5 dpc, chondrocyte density is increased by ~30%

delayed endochondral bone ossification ( J:34725 )

• at 16.0 dpc, double mutants display reduced ossification of the long bones of the fore- and hindlimbs, including complete loss of ossification in the humerus

craniofacial

abnormal craniofacial bone morphology ( J:34725 )

interparietal bone hypoplasia ( J:34725 )

• at 19.0 dpc, the interparietal bone of double mutant mice appears underdeveloped; most other cranial bones develop normally

abnormal supraoccipital bone morphology ( J:34725 )

• at 19.0 dpc, the supraoccipital bone of double mutant mice appears slightly underdeveloped

absent incisors ( J:82802 )

• a few double mutant embryos display incisors anodontia with undifferentiated mesenchymal tissue

small incisors ( J:82802 )

• most double mutant embryos exhibit incisors microdontia

abnormal tooth development ( J:82802 )

• when present, the tooth germ of double mutant embryos shows variable degrees of microdontia along with hypoplasia and disorganization of the odontoblast layer

short snout ( J:34725 )

• beginning at 15.0-16.0 dpc, double mutants display a shortened snout

limbs/digits/tail

abnormal forelimb morphology ( J:34725 )

abnormal limb bone morphology ( J:34725 )

abnormal humerus morphology ( J:34725 )

• at 16.0 dpc, the mutant humerus shows complete lack of ossification

increased diameter of humerus ( J:34725 )

• at 19.0 dpc, double mutants show abnormal thickening of the humerus

short humerus ( J:34725 )

• at 19.0 dpc, double mutants show abnormal shortening of the humerus

short radius ( J:34725 )

• at 19.0 dpc, double mutants show abnormal shortening of the radius

increased diameter of radius ( J:34725 )

• at 19.0 dpc, double mutants show abnormal thickening of the radius

short ulna ( J:34725 )

• at 19.0 dpc, double mutants show abnormal shortening of the ulna

increased diameter of ulna ( J:34725 )

• at 19.0 dpc, double mutants show abnormal thickening of the ulna

short limbs ( J:34725 )

• beginning at 15.0-16.0 dpc, double mutants have significantly shorter limbs

respiratory system

abnormal tracheal cartilage morphology ( J:34725 )

• at 18.0 dpc, some double mutants display abnormal tracheal cartilage formation, contributing to airway dysfunction and possibly neonatal lethality

abnormal breathing pattern ( J:34725 )

• prior to death, double mutant neonates exhibit breathing abnormalities and poor oxygenation

apnea ( J:34725 )

• in double mutant neonates, abnormal endocranial bone formation may result in compression of the cervical spinal canal and observed lethal apnea

growth/size/body

absent incisors ( J:82802 )

• a few double mutant embryos display incisors anodontia with undifferentiated mesenchymal tissue

small incisors ( J:82802 )

• most double mutant embryos exhibit incisors microdontia

abnormal tooth development ( J:82802 )

• when present, the tooth germ of double mutant embryos shows variable degrees of microdontia along with hypoplasia and disorganization of the odontoblast layer

short snout ( J:34725 )

• beginning at 15.0-16.0 dpc, double mutants display a shortened snout

decreased body size ( J:34725 )

• at 18.5 dpc, double mutants are up to 30% smaller than littermates

decreased fetal size ( J:34725 )

• beginning at 15.0-16.0 dpc, double mutant embryos display a significant reduction in size

distended abdomen ( J:34725 )

• beginning at 15.0-16.0 dpc, double mutants display a moderately distended abdomen

endocrine/exocrine glands

enlarged sebaceous gland ( J:82802 )

• at 4 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice frequently display hyperplasic sebaceous glands

integument

abnormal keratinocyte differentiation ( J:82802 )

• newborn double homozygotes exhibit abnormal terminal differentiation of epidermal keratinocytes

• in addition, grafts of double mutant epidermis placed onto NOD Prkdc^scid mice show aberrant keratinocyte differentiation and hyperproliferation in the basal cells of interfollicular epidermis; proliferating cells are also detected in some cells of the suprabasal layer

enlarged sebaceous gland ( J:82802 )

• at 4 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice frequently display hyperplasic sebaceous glands

abnormal awl hair morphology ( J:82802 )

abnormal guard hair morphology ( J:82802 )

abnormal zigzag hair morphology ( J:82802 )

abnormal hair follicle development ( J:82802 )

• at 4 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice frequently exhibit multiple dysplastic hair follicles sharing a single hair channel as well as multiple follicular keratin-filled cysts

underdeveloped hair follicles ( J:82802 )

• newborn double homozygotes display a developmental delay in hair follicle formation that is associated with decreased Bmp4-dependent signaling in the epidermis

• this delay is first apparent at 14.5 dpc, concomitant with a severe reduction in the number of hair germs, and persists at 16.5 and 18.5 dpc, suggesting impaired morphogenesis and development of both tylotrich and nontylotrich hair follicles

• normal hair growth is restored when grafts of double mutant epidermis are placed onto NOD Prkdc^scid mice: at 4 weeks after transplantation, mutant skin grafts show normal anagen hair follicles with normal epithelial layers and hair bulbs

• in spite of normal hair formation, mutant skin grafts display several defects in hair morphogenesis, development and cycling

abnormal hair follicle orientation ( J:82802 )

• at 4 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice frequently have twisted hair follicles lying in parallel to the epidermal surface

decreased hair follicle number ( J:82802 )

• newborn double homozygotes show a generalized reduction in the number of hair follicles

• notably, at 4 weeks after transplantation, grafts of double mutant epidermis placed onto NOD Prkdc^scid mice display a 3-fold increase in the number of hair follicles

delayed emergence of vibrissae ( J:82802 )

• at 14.5 dpc, double mutant embryos exhibit a developmental delay of whiskers

abnormal hair cycle ( J:82802 )

• at 8 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice continue to display most hair follicles in anagen as opposed to the expected resting telogen phase

parakeratosis ( J:82802 )

• at 4 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice frequently display parakeratosis

abnormal epidermis stratum granulosum morphology ( J:82802 )

• newborn double homozygotes show a decrease in the number and size of keratohyalin granules of the stratum granulosum

epidermal hyperplasia ( J:82802 )

• at 4 weeks after transplantation, double mutant skin grafts placed onto NOD Prkdc^scid mice frequently display epidermal hyperplasia

cellular

abnormal keratinocyte differentiation ( J:82802 )

• newborn double homozygotes exhibit abnormal terminal differentiation of epidermal keratinocytes

• in addition, grafts of double mutant epidermis placed onto NOD Prkdc^scid mice show aberrant keratinocyte differentiation and hyperproliferation in the basal cells of interfollicular epidermis; proliferating cells are also detected in some cells of the suprabasal layer

Genotype
MGI:3582649

cx7

• Allelic Composition: Rbl1^tm1Tyj/Rbl1⁺; Rbl2^tm1Tyj/Rbl2^tm1Tyj
• Genetic Background: involves: 129S2/SvPas * C57BL/6

growth/size/body

postnatal growth retardation ( J:34725 )

• these mutant mice exhibit only a subtle and transient growth retardation from which they recover at 3 weeks of age

limbs/digits/tail

limbs/digits/tail phenotype ( J:34725 )

N • at 16.0-19.0 dpc, these mutant embryos display normal forelimb development

Genotype
MGI:5614114

cx8

• Allelic Composition: Rbl1^tm1.1Fad/Rbl1^tm1.1Fad; Rbl2^tm1Tyj/Rbl2^tm1Tyj
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * FVB/N

cellular

cellular phenotype ( J:217445 )

N • proliferating and serum starved cells exhibit normal withdrawal from the cell cycle

craniofacial

interparietal bone hypoplasia ( J:217445 )

• small and underdeveloped

small supraoccipital bone ( J:217445 )

• small and underdeveloped

abnormal middle ear ossicle morphology ( J:217445 )

• poorly mineralized

growth/size/body

decreased body size ( J:217445 )

• despite normal weight at E18.5, rare survivors are severely runted

hearing/vestibular/ear

abnormal middle ear ossicle morphology ( J:217445 )

• poorly mineralized

limbs/digits/tail

short radius ( J:217445 )

• at E18.5

short ulna ( J:217445 )

• at E18.5

short femur ( J:217445 )

• at E18.5

short fibula ( J:217445 )

• at E18.5

short tibia ( J:217445 )

• at E18.5

mortality/aging

neonatal lethality, incomplete penetrance ( J:217445 )

• some mice die shortly after birth

postnatal lethality, complete penetrance ( J:217445 )

• all but one mouse died by 1.5 days after birth

skeleton

interparietal bone hypoplasia ( J:217445 )

• small and underdeveloped

small supraoccipital bone ( J:217445 )

• small and underdeveloped

abnormal middle ear ossicle morphology ( J:217445 )

• poorly mineralized

abnormal long bone epiphyseal ossification zone morphology ( J:217445 )

• hyperplasia of chondrocytes in the resting and proliferating zones

abnormal long bone epiphyseal plate proliferative zone ( J:217445 )

• hyperplasia of chondrocytes in the resting and proliferating zones

decreased long bone epiphyseal plate size ( J:217445 )

• slightly

decreased length of long bones ( J:217445 )

• at E18.5

short radius ( J:217445 )

• at E18.5

short ulna ( J:217445 )

• at E18.5

short femur ( J:217445 )

• at E18.5

short fibula ( J:217445 )

• at E18.5

short tibia ( J:217445 )

• at E18.5

abnormal scapular spine morphology ( J:217445 )

• short at E18.5

abnormal bone mineralization ( J:217445 )

• poorly mineralized inner ear ossicles

• however, mineralization of the long bones is normal