Rb1<tm1Tyj> Targeted Allele Detail MGI Mouse (MGI:1857242)

Rb1^tm1Tyj
Targeted Allele Detail

Nomenclature

Symbol:	Rb1^tm1Tyj
Name:	retinoblastoma 1; targeted mutation 1, Tyler Jacks
MGI ID:	MGI:1857242
Synonyms:	pRb^-, Rb-, Rb^x3t
Gene:	Rb1 Location: Chr14:73595309-73725547 bp, - strand Genetic Position: Chr14, 41.0 cM, cytoband D3

Mutation
origin

Germline Transmission:	Earliest citation of germline transmission: J:2511
Parent Cell Line:	D3 (ES Cell)
Strain of Origin:	129S2/SvPas

Mutation
description

Allele Type:	Targeted (knock-out)
Mutations:	Insertion, Intragenic deletion
	A PGK-neomycin resistance cassette replaced part of intron 3 and introduced three nucleotide changes into exon 3, creating two termination codons and a new PstI site. The authors predict translation of a truncated protein by the mutant allele. Immunoblot analysis of E12.5 brain did not detect full length RB1 protein in homozygous mice. (J:2511)

Find Mice (IMSR)

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

Carrying this Mutation:	Mouse Strains: 5 strains available Cell Lines: 0 lines available
Carrying any Rb1 Mutation:	32 strains or lines available

Expression

In Mice Carrying this Mutation:

24 assay results

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:

behavior/neurological

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cardiovascular system

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cellular

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digestive/alimentary system

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embryogenesis

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endocrine/exocrine glands

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growth/size

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hearing/vestibular/ear

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hematopoietic system

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homeostasis/metabolism

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immune system

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lethality/postnatal

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lethality/prenatal-perinatal

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life span/aging

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liver/biliary system

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muscle

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nervous system

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reproductive system

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skeleton

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skin/coat/nails

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tumorigenesis

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vision/eye

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Phenotypic
data by
genotype

Phenotypic Data by Genotype

(show or hide all phenotypic details)

Genotype	Allelic Composition	Genetic Background
hm1	Rb1^tm1Tyj/Rb1^tm1Tyj	involves: 129S2/SvPas
lethality/prenatal-perinatal lethality throughout fetal growth and development (J:105548) live homozygotes are rarely recovered at E15.5 and never at E16.5 hematopoietic system abnormal erythropoiesis (J:105548) significant decrease in the percentage of enucleated erythrocytes, indicating defective erythrocyte maturation increased nucleated erythrocyte cell number (J:81643) at E13.5, peripheral blood smears contain predominantly nucleated erythrocytes abnormal macrophage differentiation (J:105548) fetal liver macrophages exhibit defects in differentiation, as indicated by small size, lack of extensive cytoplasmic projections, and weak staining for a mature macrophage marker liver/biliary system liver hypoplasia (J:81643) at E13.5 liver cellularity is decreased and the level of apoptosis is increased nervous system abnormal fourth ventricle morphology (J:105548) detect ectopic mitosis and apoptosis in the intermediate zones of the fourth ventricle abnormal third ventricle morphology (J:105548) detect ectopic mitosis and apoptosis in the intermediate zones of the third ventricle abnormal neurogenesis (J:81643) at E13.5, proliferation is increased in the brain, dorsal root ganglia, and trigeminal ganglia increased neuron apoptosis (J:81643) at E13.5, apoptosis is increased in the brain, dorsal root ganglia, and trigeminal ganglia abnormal trigeminal ganglion morphology (J:105548) detect ectopic mitosis and apoptosis in the trigeminal ganglia abnormal dorsal root ganglion morphology (J:105548) detect ectopic mitosis and apoptosis in the dorsal root ganglia vision/eye abnormal lens development (J:81643) at E13.5, ectopic proliferating cells are seen in the interior of the lens and increased apoptosis is seen abnormal lens fiber morphology (J:105548) detect ectopic mitoses in the lens fiber compartment that is not seen in wild-type lens fiber cells are disorganized increased lens fiber apoptosis (J:105548) apoptosis is detected in the lens fiber compartment that is not seen in wild-type homeostasis/metabolism hypoxia (J:81643) expression of hypoxia-inducible genes is increased in the central nervous system at E13.5 cellular abnormal cell cycle (J:105548) MEFs exhibit an increase in the fraction of cells in the S and G2/M phases of the cell cycle abnormal cell cycle checkpoint function (J:105548) MEFs fail to efficiently trigger G1/S cell cycle arrest in response to DNA damage increased cell proliferation (J:105548) MEFs cultured at confluence exhibit an increase in cell proliferation compared to wild-type MEFs embryogenesis decreased embryo size (J:105548) abnormal placenta labyrinth morphology (J:105548) normal labyrinth architecture is disrupted the porous appearance of the labyrinth layer is absent abnormal placental transport (J:105548) exhibit defective placental transport as indicated by a 7.2% reduction of the essential fatty acid linoleic acid, arachidonic acid and docosahexaenoic acid in E14.5 embryos relative to wild-type growth/size decreased embryo size (J:105548) immune system abnormal macrophage differentiation (J:105548) fetal liver macrophages exhibit defects in differentiation, as indicated by small size, lack of extensive cytoplasmic projections, and weak staining for a mature macrophage marker skin/coat/nails pallor (J:105548)
Genotype	Allelic Composition	Genetic Background
hm2	Rb1^tm1Tyj/Rb1^tm1Tyj	involves: 129S2/SvPas * C57BL/6
lethality/prenatal-perinatal lethality throughout fetal growth and development (J:81082, J:2511) homozygous mutant embryos die between E14.5 and E15.5 (J:2511) hematopoietic system abnormal erythropoiesis (J:2511) at E13.5, homozygotes display impaired definitive erythropoiesis and fail to produce sufficient numbers of mature erythrocytes, resulting in hypoxia and eventually death abnormal erythrocyte morphology (J:2511) in vitro, mutant erythroid precursors fail to reach end-stage differentiation: small hemaglobinized colonies from mutant mice are pale and contain increased numbers of small late normoblast-like cells instead of enucleated (mature) erythrocytes similarly, mutant large erythroid colonies are pale, with <5% enucleated erythrocytes relative to wild-type (45%) low mean erythrocyte cell number (J:2511) at E13.5, wild-type embryos contain on average 45% enucleated, definitive erythrocytes; in contrast, mutant embryos only contain 6.8% enucleated cells anemia (J:2511) at E13.5, homozygotes are severely pale relative to wild-type embryos liver/biliary system abnormal liver morphology (J:2511) at E13.5, mutant livers appear lacy and largely acellular; in contrast, wild-type livers are densely packed with cells (90% of which are of erythroid lineage) small liver (J:2511) at E13.5, homozygotes display a slight reduction in liver size homeostasis/metabolism pericardial edema (J:2511) at E13.5, homozygotes display significant edema, particularly in the pericardial space skin edema (J:2511) at E13.5, edema results in damage of the dermis and underlying mesenchyme however, most non-hematopoietic tissues remain unaffected until death (~E14.5) cardiovascular system pericardial edema (J:2511) at E13.5, homozygotes display significant edema, particularly in the pericardial space skin/coat/nails skin edema (J:2511) at E13.5, edema results in damage of the dermis and underlying mesenchyme however, most non-hematopoietic tissues remain unaffected until death (~E14.5) nervous system nervous system phenotype (J:92520) normal numbers of primary neurospheres are produced from cultured E10 telencephalic neuroepithelia increased neuron apoptosis (J:2511) at E12.5, mutant embryos exhibit increased neuronal apoptosis in the spinal cord, dorsal root ganglia and parts of the hindbrain neuronal cell death occurs prior to the manifestation of the erythropoietic defect, and does not appear to be a secondary effect of anemia-induced hypoxia vision/eye vision/eye phenotype (J:2511) at E13.5, homozygotes display normal retinal development cellular increased apoptosis (J:37145) at E13.5, TUNEL analysis indicates a significant increase in apoptotic nuclei throughout the mutant nervous system (esp. dorsal ganglia), in skeletal muscle precursor cells (e.g. tongue myoblasts), lens, and to a lesser extent in liver in contrast, no significant increase in apoptosis is noted in the mutant lung or cardiac muscles increased cell proliferation (J:81082) MEFs largely fail to arrest in response to confluent growth and ~40% of the cells enter S phase behavior/neurological hunched posture (J:37145) at E13.5, 7 of 8 homozygotes display a hunchback posture skeleton abnormal cartilage morphology (J:37145) at E13.5, 7 of 8 homozygotes display a reduced cartilaginous frame (perichondrium) relative to wild-type mice
Genotype	Allelic Composition	Genetic Background
ht3	Rb1^tm1Tyj/Rb1⁺	involves: 129S2/SvPas * C57BL/6
life span/aging premature death (J:81082) all heterozygous mutant mice die between 8.5 and 13.9 months of age tumorigenesis tumorigenesis (J:2511) up to 11 months of age, none of >100 heterozygotes studied show any macroscopic sign of retinoblastoma relative to wild-type mice in addition, no precursor lesions (retinomas) are detected by indirect ophthalmology or histological evaluation increased tumor incidence (J:81082, J:2511) heterozygotes develop intermediate lobe pituitary tumors and 23/27 show c-cell thyroid tumors (J:81082) at autopsy, heterozygotes with severe wasting symptoms show large pituitary adenocarcinomas (~ 6 mm in diameter) (J:2511) consistent with the "two-hit" model proposed by Knudson, such pituitary tumors are shown to arise from cells in which the wild-type allele is absent (J:2511) growth/size cachexia (J:2511) at 8-10 months of age, a number of heterozygotes display severe wasting
Genotype	Allelic Composition	Genetic Background
ht4	Rb1^tm1Tyj/Rb1⁺	involves: 129S2/SvPas * C57BL/6J
life span/aging premature death (J:133299) median lifespan is 372 days compared to 546 days for Men1^tm1.1Ctre heterozygotes tumorigenesis increased tumor incidence (J:133299) mice exhibit tumors of the pituitary anterior and intermediate lobes (42% and 100%, respectively), metastic thyroid C-cell carcinomas (100%), and pheochromocytomas (40%) unlike wild-type mice 60% of mice exhibit lung metastasis however, no parathyroid adenomas are observed pheochromocytoma (J:133299) in 40% of mice lung tumor (J:133299) in 60% of mice
Genotype	Allelic Composition	Genetic Background
ht5	Rb1^tm1Tyj/Rb1^tm2Tyj	chimera involves: 129S2/SvPas * C57BL/6
growth/size cachexia (J:59268) display severe wasting and become moribund by 3-4 months tumorigenesis pituitary adenoma (J:59268) severe adenocarcenomas by 3-4 months of age in chimeric mice derived from the intermediate lobe preneoplasia (J:59268) hyperchromatic cells are found in the adrenal medulla of chimeric mice indicating neoplastic lesions nervous system nervous system phenotype (J:59268) examined in chimeric mice abnormal Purkinje cell morphology (J:59268) cells with enlarged nuclei ectopic Purkinje cell (J:59268) displaced Purkinje cells thin granule layer (J:59268) liver/biliary system abnormal hepatocyte morphology (J:59268) abnormally large nuclei in chimeric mice vision/eye vision/eye phenotype (J:59268) examined in chimeric mice no retinoblastomas normal retinal architecture cataracts (J:59268) in all mice examined evidence of cataracts when eyes first open at 1 week of age characterized by a posterior migration of the lens epithelium associated with bladder cell formation and sometimes with calcification lens of newborns highly disorganized with many pyknotic cells
Genotype	Allelic Composition	Genetic Background
ht6	Rb1^tm1Dwg/Rb1^tm1Tyj	involves: 129/Sv * 129S2/SvPas * C57BL/6
lethality/prenatal-perinatal lethality throughout fetal growth and development (J:105548) survive as long as homozygous Rb1^tm1Dwg mice, with 2 of 18 dead at E15.5 and 4 of 7 dead at E17.5 growth/size decreased embryo size (J:105548) although embryos are smaller than wild-type, they are larger than age-matched homozygous Rb1^tm1Tyj embryos hematopoietic system abnormal erythropoiesis (J:105548) small percentage of erythrocytes exhibit enucleating defects at E17.5, indicating a less severe erythrocyte maturation defect than seen in homozygous Rb1^tm1Tyj mice skin/coat/nails pallor (J:105548) although embryos are paler than wild-type, they exhibit improved coloration over that seen in homozygous Rb1^tm1Tyj embryos embryogenesis decreased embryo size (J:105548) although embryos are smaller than wild-type, they are larger than age-matched homozygous Rb1^tm1Tyj embryos
Genotype	Allelic Composition	Genetic Background
cn7	Rb1^tm1Tyj/Rb1^tm2Brn Rbl1^tm1Tyj/Rbl1^tm1Tyj Trp53^tm1Brn/Trp53^tm1Brn Tg(Chx10-EGFP/cre,-ALPP)2Clc/0	involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6 * SJL
vision/eye abnormal eye anterior chamber (J:120315) tumor cells that invade the anterior eye chamber beneath the cornea are densely packed stage II cells surrounded by sparse regions of plexus with no synaptic densities or vesiclesin in the plexus or rosettes of these cells tumor cells have abundant mitochondria and mitotic figures; some rosettes have a central plexus made up of large, undifferentiated processes, with other rosettes having a central plexus containing neurons and synapses abnormal eye posterior chamber (J:120315) areas of the plexus within the posterior chamber are composed of neuron-like processes having synaptic structures similar to horizontal/amacrine cells; this is seen in smaller areas of plexus in tumors processes are usually smaller in diameter (<0.5 um) but large ones of 1-3 um are observed occasionally; variety of synaptic arrangements occur and all types can be found in contacts among processes, while ribbon synapses are seen only in areas near photoreceptor cell bodies abnormal retina morphology (J:120315) significant disruptions in retinal morphology are observed by P12 to 13 in diseased eyes, retina blastoma cells rupture the inner limiting membrane (ILM), particularly by the apex of vitreal protrusions that may be present; at these points, tumor cell bodies and associated vasculature can be seen tumorigenesis retinoblastoma (J:120315) mice have much more aggressive, invasive form of retinoblastoma than Trp53-sufficient compound mutants; tumor size varies with age and genotype an early-stage tumor displayed a pronounced vitreal protrusion in one animal, and contained structures resembling neuronal processes like those in the plexiform layer of the normal retina in tumors, proteins usually found in amacrine/horizontal cells, including Gad65, Snap25, Calbindin, vGlut-1, E-cadherin, N-cadherin, synapsin, and Syntaxin-1 are expressed; these cells are considered to be differentiated cells positive for amacrine/horizontal cell markers (1.7-3.6 x 10⁶ cells/tumor) are much more numerous than number of amacrine/horizontal cells in a normal retina regions of tumors negative for amacrine/horizontal markers contain more densely packed nuclei
Genotype	Allelic Composition	Genetic Background
cn8	Rb1^tm1Tyj/Rb1^tm2Brn Rbl1^tm1Tyj/Rbl1^tm1Tyj Trp53^tm1Brn/Trp53^tm1Tyj Tg(Chx10-EGFP/cre,-ALPP)2Clc/0	involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6 * SJL
vision/eye abnormal eye anterior chamber (J:120315) tumor cells that invade the anterior eye chamber beneath the cornea are densely packed stage II cells surrounded by sparse regions of plexus with no synaptic densities or vesiclesin in the plexus or rosettes of these cells tumor cells have abundant mitochondria and mitotic figures; some rosettes have a central plexus made up of large, undifferentiated processes, with other rosettes having a central plexus containing neurons and synapses abnormal eye posterior chamber (J:120315) areas of the plexus within the posterior chamber are composed of neuron-like processes having synaptic structures similar to horizontal/amacrine cells; this is seen in extensive plexus areas of tumors tumorigenesis retinoblastoma (J:120315) retinoblastoma cells that express amacrine/horizontal cell markers also extend processes and form synapses; some of these Golgi-Cox-labeled cells extend 1-3 long main processes with further neurite branching characteristic of horizontal or wide-field amacrine cells, while more (nearly half of ) labeled cells extend a main process with extensive neurite outgrowth characteristic of amacrine cells, and the remaining cells are less differentiated with short, unbranched neurites these labeled cells are mainly found near the tumor origin, while fewer are present toward the lens and anterior chamber cellular abnormal cell proliferation (J:120315) a substantial proportion of tumor cells expressing amacrine/horizontal cell markers are proliferating as shown by labeled thymidine incorporation
Genotype	Allelic Composition	Genetic Background
cn9	Rb1^tm1Tyj/Rb1^tm2Brn Rbl1^tm1Tyj/Rbl1⁺ Trp53^tm1Brn/Trp53^tm1Brn Tg(Chx10-EGFP/cre,-ALPP)2Clc/0	involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6 * SJL
vision/eye abnormal retina morphology (J:120315) mice have much more aggressive, invasive form of retinoblastoma than Trp53-sufficient compound mutants, but onset is delayed compared to that observed in Rbl1 homozygous compound mutants tumor size varies with age and genotype mice show rapid filling of the vitreal cavity with densely packed tumor cells and rosettes; in the tumors, there is an overabundance of stage II retinoblastoma cells near outer surface of retina near tumor origin site, there are regions of plexus with synaptic densities and synaptic vesicles, indistinguishable from the Rb1;Rbl1 mutants that are wild-type for Trp53 tumorigenesis retinoblastoma (J:120315) significant disruptions in retinal morphology are observed by P12 to 13
Genotype	Allelic Composition	Genetic Background
cn10	Rb1^tm1Tyj/Rb1^tm2Brn Rbl1^tm1Tyj/Rbl1⁺ Tg(Chx10-EGFP/cre,-ALPP)2Clc/0	involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6 * SJL
nervous system decreased retinal photoreceptor cell number (J:120315) mice with retinoblastoma tumors are characterized by pronounced loss of photoreceptor cells tumorigenesis retinoblastoma (J:120315) retinoblastoma cells that express amacrine/horizontal cell markers also extend processes and form synapses; some of these Golgi-Cox-labeled cells extend 1-3 long main processes with further neurite branching characteristic of horizontal or wide-field amacrine cells, while more (nearly half of ) labeled cells extend a main process with extensive neurite outgrowth characteristic of amacrine cells, and the remaining cells are less differentiated with short, unbranched neurites these labeled cells are mainly found near the tumor origin, while fewer are present toward the lens and anterior chamber tumors show appearance of unique populations of undifferentiated tumor-like cells, and extensive formation of plexiform regions in a large tumor that filled much of the vitreal space contained two cell types: some cells are stage I retinoblastoma cells with pale, round nuclei resembling differentiated neurons and always associated with a plexus or tightly-packed stage II retinoblastoma cells with irregular nuclei with little or no plexus associated with individual cells rosettes in retinoblastomas are usually composed of stage I cells with a central plexus, but are adjacent to clusters of stage II cells plexus regions of tumors show mitotic figures and apoptotic cells; plexus regions also contained synaptic densities and associated synaptic vesicles vision/eye abnormal eye posterior chamber (J:120315) areas of the plexus within the posterior chamber are composed of neuron-like processes having synaptic structures similar to horizontal/amacrine cells; this is seen in smaller areas of plexus in tumors processes are usually smaller in diameter (<0.5 um) but large ones of 1-3 um are observed occasionally; variety of synaptic arrangements occur and all types can be found in contacts among processes, while ribbon synapses are seen only in areas near photoreceptor cell bodies abnormal retina morphology (J:120315) significant disruptions in retinal morphology are observed by P12 to 13 decreased retinal photoreceptor cell number (J:120315) mice with retinoblastoma tumors are characterized by pronounced loss of photoreceptor cells
Genotype	Allelic Composition	Genetic Background
cx11	E2f1^tm1Njd/E2f1^tm1Njd Rb1^tm1Tyj/Rb1^tm1Tyj	either: 129S2/SvPas or (involves: 129S2/SvPas * C57BL/6)
lethality/prenatal-perinatal prenatal lethality (J:47108) no double homozygotes recovered after birth
Genotype	Allelic Composition	Genetic Background
cx12	E2f1^tm1Njd/E2f1⁺ Rb1^tm1Tyj/Rb1^tm1Tyj	either: 129S2/SvPas or (involves: 129S2/SvPas * C57BL/6)
lethality/prenatal-perinatal prenatal lethality (J:47108) no mice of this genotype recovered after birth
Genotype	Allelic Composition	Genetic Background
cx13	E2f1^tm1Njd/E2f1⁺ Rb1^tm1Tyj/Rb1⁺	either: 129S2/SvPas or (involves: 129S2/SvPas * C57BL/6)
tumorigenesis increased tumor incidence (J:47108) develop grossly detectable pituitary tumors thyroid adenoma (J:47108) fewer thyroid C-cell adenomas than in Rb1^tm1Tyj heterozygotes life span/aging premature death (J:47108) increased survival relative to Rb1^tm1Tyj heterozygotes, 11.6 months on a 129 background and up to 12.6 months on a mixed background
Genotype	Allelic Composition	Genetic Background
cx14	E2f1^tm1Njd/E2f1^tm1Njd Rb1^tm1Tyj/Rb1⁺	either: 129S2/SvPas or (involves: 129S2/SvPas * C57BL/6)
tumorigenesis increased tumor incidence (J:47108) only about 62% develop pituitary tumors pituitary tumors are smaller than Rb1^tm1Tyj heterozygotes but histologically indistinguishable thyroid adenoma (J:47108) fewer thyroid C-cell adenomas than in Rb1^tm1Tyj heterozygotes hemangioma (J:47108) endocrine/exocrine glands adrenal medulla hyperplasia (J:47108) abnormal thyroid gland morphology (J:47108) thyroid gland degeneration after 14 months of age reproductive system uterine hemorrhage (J:47108) life span/aging premature death (J:47108) increased survival relative to Rb1^tm1Tyj heterozygotes, 15.2 months on a 129 background and up to 17 months on a mixed background cardiovascular system uterine hemorrhage (J:47108)
Genotype	Allelic Composition	Genetic Background
cx15	Rb1^tm1Tyj/Rb1^tm1Tyj Rbl1^tm1Mru/Rbl1^tm1Mru	involves: 129S2/SvPas * 129S4/SvJae * BALB/c * C57BL/6
nervous system increased neuronal precursor cell number (J:92520) mice exhibit increased neuronal precursor numbers due to increased proliferation cultured E10 telencephalic neuroepithelia produces more primary neurospheres than cultures from wild-type mice
Genotype	Allelic Composition	Genetic Background
cx16	Men1^tm1.1Ctre/Men1⁺ Rb1^tm1Tyj/Rb1⁺	involves: 129S2/SvPas * 129S6/SvEvTac * C57BL/6J * FVB/N
life span/aging premature death (J:133299) median lifespan is 402 days compared to 546 days for Men1^tm1.1Ctre heterozygotes tumorigenesis increased tumor incidence (J:133299) mice exhibit pituitary anterior lobe tumors (40%), pituitary intermediate lobe tumors (96%), thyroid C-cell carcinomas (96%), metastasis in the lungs (70%), parathyroid gland tumor (50%), adrenal pheochromocytoma (45%), adrenal cortical tumor (10%), and pancreatic islet tumor (55%) parathyroid adenoma (J:133299) 50% of mice exhibit parathyroid gland tumors pheochromocytoma (J:133299) in 45% of mice lung tumor (J:133299) in 70% of mice pancreas tumor (J:133299) 55% of mice exhibit pancreatic islet tumors
Genotype	Allelic Composition	Genetic Background
cx17	E2f4^tm1Lees/E2f4^tm1Lees Rb1^tm1Tyj/Rb1⁺	involves: 129S2/SvPas * C57BL/6
life span/aging premature death (J:81082) two mutant mice died at early stages (2.7 and 5.4 months) as a result of increased susceptibility to infection, however majority of mutant mice survived at least until the window of lethality of the single heterozygous mutant Rb1 mice and a significant fraction lived to an age comparable to wild-type tumorigenesis decreased tumor incidence (J:81082) suppressed tumor formation compared to single heterozygous mutant Rb1 mice, with no mutants developing pituitary tumors prior to 16 months of age and significantly lower incidence of pituitary tumors thereafter and only 1/17 mutants developing a c-cell thyroid tumor immune system increased susceptibility to infection (J:81082) two mutant mice died at early stages (2.7 and 5.4 months) as a result of increased susceptibility to infection, however showed no evidence of tumorigenic lesions in these mice
Genotype	Allelic Composition	Genetic Background
cx18	E2f4^tm1Lees/E2f4⁺ Rb1^tm1Tyj/Rb1⁺	involves: 129S2/SvPas * C57BL/6
life span/aging premature death (J:81082) died by 18 months of age compared to 20-27 months in wild-type tumorigenesis increased tumor incidence (J:81082) developed pituitary and thyroid tumors that were comparable to those arising in single heterozygous mutant Rb1 mice with respect to both incidence and size
Genotype	Allelic Composition	Genetic Background
cx19	Rb1^tm1Tyj/Rb1⁺ Rbl1^tm1Tyj/Rbl1^tm1Tyj	involves: 129S2/SvPas * C57BL/6
lethality/postnatal postnatal lethality (J:34058) at 1 week of age, mutant pups are obtained at a significantly lower frequency (19%) than expected (25%) most mutants die within the first 3 weeks of age, with only about 25% surviving beyond 3 weeks life span/aging premature death (J:34058) females displaying vaginal atresia accumulate fluid in the uterus and die between 4 and 6 months of age similar to Rb1^tm1Tyj heterozygotes, any surviving mutant mice eventually die of pituitary tumors after 12 months growth/size decreased body size (J:34058) mutant pups become runted several days after birth decreased body weight (J:34058) beginning at ~1 week, mutant pups appear severely growth retarded, averaging 50% of the weight of control littermates mutants surviving beyond 3 weeks of age gain weight slowly, averaging 70-90% of normal weight at 3 months postnatal growth retardation (J:34058) although mutant pups are of approximately uniform size at birth, a number of pups display severe growth retardation, with weight differences persisting for several weeks distended abdomen (J:34058) females displaying vaginal atresia have a distended abdomen as a result of fluid accumulation in the uterus tumorigenesis increased tumor incidence (J:34058) similar to Rb1^tm1Tyj heterozygotes, all surviving mutant mice develop large pituitary adenocarcinomas of the intermediate lobe reproductive system abnormal perineum morphology (J:34058) females displaying vaginal atresia have a distended perineum as a result of fluid accumulation in the uterus vagina atresia (J:34058) ~75% of mutant females display vaginal atresia whereas the majority of mutant males surviving beyond 3 weeks of age are fertile and appear normal up to 12 months in affected females, the vaginal opening is absent; however, the rest of the reproductive tract appears unaffected vision/eye abnormal retina morphology (J:34058) at 4-6 months, all mutant mice display retinal dysplasia; both eyes are affected in 11 out of 12 mutants typically, each eye contains 5-7 individual lesions composed of small white bodies (usually in clusters), indicating retinal pathology abnormal retinal photoreceptor morphology (J:34058) as early as 4 days after birth, mutant newborns exhibit mild, yet significant, disruptions of the retinal photoreceptor layer nervous system abnormal retinal photoreceptor morphology (J:34058) as early as 4 days after birth, mutant newborns exhibit mild, yet significant, disruptions of the retinal photoreceptor layer digestive/alimentary system abnormal perineum morphology (J:34058) females displaying vaginal atresia have a distended perineum as a result of fluid accumulation in the uterus
Genotype	Allelic Composition	Genetic Background
cx20	Rb1^tm1Tyj/Rb1^tm1Tyj Rbl1^tm1Tyj/Rbl1^tm1Tyj	involves: 129S2/SvPas * C57BL/6
lethality/prenatal-perinatal embryonic lethality during organogenesis (J:34058) at E10.5, 2 out of 10 double mutants are found dead and 2 are noticeably smaller; also, 9 out of 19 double mutants die at E11.5, that is 2 days earlier than mice homozygous for Rb1^tm1Tyj alone by E12.5, 7 out of 8 double mutant embryos are either dead or in various stages of resorption cellular increased apoptosis (J:34058) at E11.5, double mutant embryos exhibit a significantly high frequency of pyknotic nuclei (i.e. apoptosis) in the CNS; in contrast, single Rb1^tm1Tyj homozygotes show extensive CNS apoptosis at later stage (E13.5) at E12.5 (but not E11.5), a viable double mutant (1 out of 8) exhibits abnormally high levels of apoptosis in the liver and CNS; in contrast, single Rb1^tm1Tyj homozygotes show extensive liver apoptosis at later stage embryogenesis decreased embryo size (J:34058) at E11.5 days, 2 out of 19 double mutant embryos are significantly smaller than control embryos abnormal vitelline vasculature (J:34058) at E11.5, viable double mutant embryos exhibit disorganization of the endothelial linings of yolk sac vessels pale yolk sac (J:34058) at E11.5, viable double mutant embryos show a significant reduction of erythrocytes in the yolk sac blood vessels growth/size decreased embryo size (J:34058) at E11.5 days, 2 out of 19 double mutant embryos are significantly smaller than control embryos muscle muscle phenotype (J:34058) at E12.5, double mutant embryos show normal myogenic commitment and differentiation
Genotype	Allelic Composition	Genetic Background
cx21	Rb1^tm1Tyj/Rb1⁺ Rbl1^tm1Tyj/Rbl1⁺	involves: 129S2/SvPas * C57BL/6
life span/aging premature death (J:34058) similar to Rb1^tm1Tyj heterozygotes, mice heterozygous for both Rb1^tm1Tyj and Rbl1^tm1Tyj die from tumors in the intermediate lobe of the pituitary gland at ~12 months of age tumorigenesis increased tumor incidence (J:34058) double heterozygotes develop large pituitary tumors of the intermediate lobe that are comparable to those arising in single Rb1^tm1Tyj heterozygotes with respect to both incidence and size such pituitary tumors are shown to arise from cells in which the wild-type allele of Rb1 is absent, whereas the wild-type allele of Rbl1 is retained
Genotype	Allelic Composition	Genetic Background
cx22	Rb1^tm1Tyj/Rb1⁺ Trp53^tm1Tyj/Trp53⁺	involves: 129S2/SvPas * C57BL/6
life span/aging premature death (J:19542) the mean age of survival of double heterozygotes is slightly reduced relative to mice heterozygous for Rb1^tm1Tyj alone (9 months vs 11 months) tumorigenesis increased tumor incidence (J:19542) 8% of a total of 12 individual double heterozygotes analyzed displayed bronchial hyperplasia; neither lymphomas nor retinal dysplasia were observed each of 67 double heterozygotes analyzed developed pituitary tumors of the intermediate lobe; ~75% of these mice also developed medullary thyroid tumors in nearly all double heterozygotes with pituitary and thyroid tumors, the wild-type allele of Rb1 is lost whereas the wild-type allele of Trp53 is retained one of 7 individual double heterozygotes analyzed displayed a single pinealoblastoma (not detected in single heterozygotes); the wild-type alleles of both Rb1 and Trp53 were lost in this piineal tumor carcinoma (J:19542) 14% of a total of 14 individual double heterozygotes analyzed displayed islet cell carcinomas (not detected in single heterozygotes) notably, the wild-type alleles of both Rb1 and Trp53 were lost in tumors of the islet cells of the pancreas sarcoma (J:19542) 6% of a total of 67 individual double heterozygotes analyzed displayed anaplastic sarcomas such tumors were shown to be more aggressive and arise at an earlier age than those occurring in single Trp53^tm1Tyj heterozygotes notably, the wild-type alleles of both Rb1 and Trp53 were lost in these anaplastic sarcomas leiomyosarcoma (J:19542) one of 7 individual double heterozygotes analyzed displayed a leiomyosarcoma pancreas tumor (J:19542) 14% of a total of 14 individual double heterozygotes analyzed displayed islet cell carcinomas (not detected in single heterozygotes)
Genotype	Allelic Composition	Genetic Background
tg23	Apaf1^tm1Mak/Apaf1^tm1Mak Rb1^tm1Tyj/Rb1^tm1Tyj Tg(Rb1)#Blg/0	involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6
hearing/vestibular/ear increased cochlear hair cell number (J:98518) at E18.5, mutant mice display a similar extent of cochlear hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg increased vestibular hair cell number (J:98518) at E18.5, mutant mice display a similar extent of vestibular hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg nervous system increased cochlear hair cell number (J:98518) at E18.5, mutant mice display a similar extent of cochlear hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg increased vestibular hair cell number (J:98518) at E18.5, mutant mice display a similar extent of vestibular hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg
Genotype	Allelic Composition	Genetic Background
tg24	Rb1^tm1Tyj/Rb1^tm1Tyj Tg(Rb1)#Blg/0	involves: 129S2/SvPas * 129S4/SvJae * C57BL/6
hearing/vestibular/ear increased cochlear hair cell number (J:98518) at E18.5, mutant mice display a similar extent of cochlear hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg increased vestibular hair cell number (J:98518) at E18.5, mutant mice display a similar extent of vestibular hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg nervous system increased cochlear hair cell number (J:98518) at E18.5, mutant mice display a similar extent of cochlear hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg increased vestibular hair cell number (J:98518) at E18.5, mutant mice display a similar extent of vestibular hair cell overproduction relative to mice that are homozygous for Rb1^tm1Tyj and hemizygous for Tg(Rb1)#Blg
Genotype	Allelic Composition	Genetic Background
tg25	Rb1^tm1Tyj/Rb1^tm1Tyj Tg(Rb1)#Blg/0	involves: 129S2/SvPas * C57BL/6
lethality/prenatal-perinatal perinatal lethality (J:37145) mutant mice die at birth, indicating partial rescue of the embryonic lethality observed in Rb1^tm1Tyj homozygotes at E13.5-E14.5 muscle abnormal myogenesis (J:37145) at E16.5-P0, mutant mice display abnormal myogenesis, with shorter myotubes relative to control mice strikingly, when present, mutant myotubes are widely dispersed, and contain enlarged nuclei that are 2-4 times longer than normal the number of elongated nuclei increases with time, approaching ~2% and >10% of the myotomal nuclei at E17.5 and E18.5, respectively at E17.5, BrdU staining indicates that mutant giant nuclei continue to actively synthesize DNA within myotubes, at a stage when DNA synthesis would have normally ceased abnormal skeletal muscle morphology (J:37145) at E16.5-E18.5, TUNEL analysis indicates a significant increase of apoptotic nuclei in mutant skeletal muscles prior to myoblast fusion in contrast, no significant increase in apoptosis is noted in mutant cardiac muscles abnormal skeletal muscle fiber morphology (J:37145) at E17.5, the myofibrils of mutant limb and tongue muscles are shorter and less abundant, although individual sarcomeric units appear intact decreased skeletal muscle mass (J:37145) at birth, mutants exhibit reduced skeletal muscle mass decreased skeletal muscle fiber density (J:37145) at E16.5-P0, mutant mice display reduced muscle fiber density in axial, tongue, and limb muscles behavior/neurological hunched posture (J:37145) at E16.5 and P0, mutants display a typical hunchback posture however, in contrast to Rb1^tm1Tyj homozygotes, the perichondrium appears normal at E13.5 abnormal stationary movement (J:37145) at birth, mutants fail to move skeleton abnormal spine curvature (J:37145) at E18.5, mutant mice lack a normal cervical curvature however, bones are present and normal in shape vision/eye abnormal lens development (J:37145) at birth, mutant mice exhibit impaired lens development abnormal lens fiber morphology (J:37145) at E17.5-P0, mutant mice display significant degeneration of the lens fibers cellular polyploidy (J:98518) in addition to aberrant cochlear and vestibular hair cell proliferation, E18.5 mutant mice exhibit multinucleated and enlarged hair cells in the inner ear sensory epithelia increased mitotic index (J:98518) unlike control mice where cells of the organ of Corti and almost all cells of the greater epithelial ridge are postmitotic at E18.5, mutants show ectopic mitoses in the greater epithelial ridge and the region of cochlear inner and outer HCs in addition, high numbers of mitotic vestibular hair cells are detected in mutant utricular, saccular, and ampullary sensory epithelia increased apoptosis (J:37145, J:98518) at E16.5-E18.5, TUNEL analysis indicates a significant increase in apoptotic nuclei in mutant axial and tongue muscles (J:37145) at E17.5 and E18.5, supernumerary cochlear and vestibular HC production is partially compensated by increased apoptosis in mutant inner ear sensory epithelia (J:98518) hematopoietic system abnormal erythropoiesis (J:37145) in contrast to Rb1^tm1Tyj homozygotes which fail to undergo enucleation of red blood cells, partially rescued mutant mice display only a slight delay in enucleation, with ~2-4% nucleated red blood cells present at E18.5 nervous system nervous system phenotype (J:37145) at E17.5-P0, mutant mice show a near normal neurogenesis, as shown by normal expression of neuronal markers in brain, trigeminal ganglia, retina, motor neurons, and dorsal root ganglia increased cochlear hair cell number (J:98518) at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating cochlear HCs at E18.5, the upper basal turn of mutant cochleas shows a 6-fold increase in the numbers of HC nuclei relative to controls at birth, mutants display ectopic mitoses in the greater epithelial ridge and the region of cochlear IHCs and OHCs, not present in control mice most mitotic cochlear HCs are located near the lumen, while some are found in deeper epithelial layers increased mitotic activity and overproduction of cochlear HCs is first evident at E15.5 at E17.5 and E18.5, supernumerary cochlear HC production is partially compensated by increased apoptosis increased cochlear inner hair cell number (J:98518) at E18.5, mutant IHCs are actively cycling, displaying a rounded morphology, typical of dividing cells increased cochlear outer hair cell number (J:98518) at E18.5, mutant OHCs are actively cycling, displaying a rounded morphology, typical of dividing cells abnormal vestibular hair cell morphology (J:98518) at E17.5 and E18.5, mutants exhibit a hyperplastic vestibular sensory epithelium due to overproduction of HCs HCs are abnormally intermixed with supporting cells in the middle layers while the basal part of the epithelium is filled with supernumerary HCs some vestibular HCs are mislocated through the basal lamina into the mesenchyme a distinct pathology, including multinucleated and enlarged HCs, apoptosis, and infiltration of HCs into the mesenchyme is observed increased vestibular hair cell number (J:98518) at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating vestibular HCs at E18.5, mutant vestibular HCs are actively cycling, displaying a rounded morphology, typical of dividing cells most mitotic vestibular HCs are located at the lumenal surface, but some are found in deeper epithelial levels and in mesenchyme increased mitotic activity and overproduction of vestibular HCs is first evident at E14.5 at E17.5 and E18.5, supernumerary vestibular HC production is partially compensated by increased apoptosis abnormal vestibular hair cell stereociliary bundle morphology (J:98518) at birth, mutants display abnormal stereociliary bundle morphologies, particularly in the utricle supernumerary vestibular HCs in the deeper epithelial layers and in mesenchyme exhibit disorganized cilia-like protusions and loss of the apicobasal polarity however, near-normal stereociliary bundles are also observed, often in ampullae hearing/vestibular/ear abnormal organ of Corti (J:98518) at E17.5 and E18.5, mutant mice exhibit a thickened greater epithelial ridge and a hyperplastic organ of Corti due to excessive hair cell (HC) formation, esp. in the basal half of the cochlea however, mutant cochlear HCs exhibit a normal profile of molecules involved in differentiation and maturation increased cochlear hair cell number (J:98518) at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating cochlear HCs at E18.5, the upper basal turn of mutant cochleas shows a 6-fold increase in the numbers of HC nuclei relative to controls at birth, mutants display ectopic mitoses in the greater epithelial ridge and the region of cochlear IHCs and OHCs, not present in control mice most mitotic cochlear HCs are located near the lumen, while some are found in deeper epithelial layers increased mitotic activity and overproduction of cochlear HCs is first evident at E15.5 at E17.5 and E18.5, supernumerary cochlear HC production is partially compensated by increased apoptosis increased cochlear inner hair cell number (J:98518) at E18.5, mutant IHCs are actively cycling, displaying a rounded morphology, typical of dividing cells increased cochlear outer hair cell number (J:98518) at E18.5, mutant OHCs are actively cycling, displaying a rounded morphology, typical of dividing cells increased organ of Corti supporting cell number (J:98518) at E17.5 and E18.5, supporting cell numbers are increased, but not to the extent of HC overproduction at E18.5, the upper basal turn of mutant cochleas shows a 3-fold increase in the numbers of Deiters' plus pillar cells found below HCs relative to controls however, no ectopic mitoses are detected in the mutant supporting cell layer abnormal vestibular hair cell morphology (J:98518) at E17.5 and E18.5, mutants exhibit a hyperplastic vestibular sensory epithelium due to overproduction of HCs HCs are abnormally intermixed with supporting cells in the middle layers while the basal part of the epithelium is filled with supernumerary HCs some vestibular HCs are mislocated through the basal lamina into the mesenchyme a distinct pathology, including multinucleated and enlarged HCs, apoptosis, and infiltration of HCs into the mesenchyme is observed increased vestibular hair cell number (J:98518) at E17.5 and E18.5, mutant mice exhibit excessive proliferation of differentiating vestibular HCs at E18.5, mutant vestibular HCs are actively cycling, displaying a rounded morphology, typical of dividing cells most mitotic vestibular HCs are located at the lumenal surface, but some are found in deeper epithelial levels and in mesenchyme increased mitotic activity and overproduction of vestibular HCs is first evident at E14.5 at E17.5 and E18.5, supernumerary vestibular HC production is partially compensated by increased apoptosis abnormal vestibular hair cell stereociliary bundle morphology (J:98518) at birth, mutants display abnormal stereociliary bundle morphologies, particularly in the utricle supernumerary vestibular HCs in the deeper epithelial layers and in mesenchyme exhibit disorganized cilia-like protusions and loss of the apicobasal polarity however, near-normal stereociliary bundles are also observed, often in ampullae abnormal utricular macula morphology (J:98518) at birth, the mutant utricular sensory epithelium is hyperplastic due to an excess of HCs, some of which have penetrated into the mesenchyme
Genotype	Allelic Composition	Genetic Background
tg26	Rb1^tm1Tyj/Rb1⁺ Tg(S100b-v-erbB)4496Waw/0	involves: 129S2/SvPas * C57BL/6J * DBA/2J * FVB/N
tumorigenesis increased tumor incidence (J:82649) mice develop gliomas in the same pattern and with the same pathology as in Tg(S100b-v-erbB)4496Waw mice

Notes

This is one of several targeted null mutations of Rb1 that have been created. Results appear to be similar for all the mutations (J:2498, J:2511, J:2516). Heterozygotes for the mutations show no predisposition to retinoblastoma. Homozygotes die in utero with neuronal and hematopoietic system abnormalities. Transfer of a human RB1 mini-transgene into the mutant mice corrects the defects (J:2516). On the other hand, transfer of the human gene into mice with a normal Rb1 genotype, causing overexpression of the gene product, produces mice dwarfed in proportion to the number of extra RB1 copies they carry (J:15042). Homozygous Rb^1tm1Tyj mutant mice given a transgene producing low levels of Rb1 product survive to birth, but die at that stage due to failure of myogenesis. Myoblasts undergo massive apoptosis, and surviving cells do not undergo terminal differentiation (J:37145).

References

Original:	J:2511 Jacks T et al., "Effects of an Rb mutation in the mouse [see comments]" Nature 1992 Sep 24;359(6393):295-300
All:	95 reference(s)

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