Overview

Also Known As:inversion of embryonic turning

Mice homozygous for situs inversus (reversal of left-right polarity/left-right reversal of abdominal visceral organs) exhibit polycystic kidney disease (PKD), severe jaundice, and die by seven days of age. Specifically, the stomach and spleen are located on anatomical right instead of left, and the heart, lungs, and liver are mirror-image left-right inversions. These mice may be useful for studying polycystic kidney disease (PKD) and the specification of left-right polarity during vertebrate development.

Donating Investigator

Paul A Overbeek, Baylor College of Medicine

Genetic overview

Genetic Background	Generation

Invs^inv

Allele Type
Transgenic

View Genetics

Research Applications

Developmental Biology Research
Mouse/Human Gene Homologs
Internal/Organ Research

View All Research Applications

Details

Detailed Description

Mice heterozygous for this mutation are viable and fertile with no gross phenotypic abnormalities. Homozygous mice exhibit severe jaundice, do not increase in size or weight after birth, and die by seven days of age. Homozygous mice display a common pattern of situs inversus (reversal of left-right polarity/left-right reversal of abdominal visceral organs). Specifically, the stomach and spleen are located on anatomical right instead of left, and the heart, lungs, and liver are mirror-image left-right inversions. Homozygous mice have polycystic kidney disease (PKD) characterized by significant kidney pathology with dilated tubules and abnormal glomeruli. Lower incidence of other abnormalities are also reported for homozygous mice; including polysplenia and heterotaxia (normal cardiovascular orientation but inverted abdominal viscera). No defects of the dynein arms in trachea cilia are reported. These mice may be useful for studying polycystic kidney disease (PKD) and the specification of left-right polarity during vertebrate development.

Development

The Ty811C transgene was designed with a tyrosinase minigene containing the tyrosinase upstream regulatory sequences (2.25 kb from the BALB/c tyrosinase promoter and the first 65 bp of exon 1) and a chimeric cDNA made with (from 5' to 3') the upstream part of the C57BL/6-derived Tyrs-J (cysteine at amino acid 103) sequence ligated at a central ScaI site to the downstream part of the DBA/2-derived tyrosinase (valine at amino acid 346). This Ty811C transgene was microinjected into one-cell-stage embryos from albino FVB/N mice. Transgenic mice can be identified by the rescue of albino phenotype (coat color and eye pigmentation). One line of mice with light brown fur pigmentation were assigned as OVE210. Homozygous OVE210 mice die within one week of birth with left-right reversal of abdominal visceral organs. The OVE210 mice were found to have a two transgene copies at a single integration site, and the recessive mutant allele was called inversion of embryonic turning (inv). The transgene integration created a small duplication and 47 kb deletion in the proximal region of chromosome 4; this deleted exons 3-11 (causing a frameshift in the remaining coding segment) of the inversin (Invs) gene. These mice were then backcrossed to FVB/NJ mice for several generations prior to arrival at The Jackson Laboratory Repository. Upon arrival, mice were bred with FVB/NJ inbred mice for at least one generation to establish the colony.

Control Suggestions

Wild-type from the colony
001800 FVB/NJ

Additional Information

Considerations for Choosing Controls

Selected References

Yokoyama T; Copeland NG; Jenkins NA; Montgomery CA; Elder FF; Overbeek PA. 1993. Reversal of left-right asymmetry: a situs inversus mutation [see comments] Science 260(5108):679-82PubMed: 8480178 MGI: J:4934

View All References

Genetics

Invs^inv

Allele Symbol: Invs^inv

Allele Name	inversion of embryonic turning
Allele Type	Transgenic
Allele Synonym(s)	inv; inv^-
Gene Symbol and Name	Invs, inversin
Gene Synonym(s)
Strain of Origin	FVB/N
Chromosome	4
General Note	This is the only situs inversus mutation in which the asymmetries occur 100% of the time. Transgenic complementation studies demonstrated that the Invs gene alone corrects the inv mutation, and should be considered the gene responsible for the inv phenotype (J:49759, J:50117).
Molecular Note	The inv mutation was caused by a transgene insertion mutagenic event that resulted in a small duplication and a 47-kb deletion. This deletion eliminated exons 3-11, causing a frameshift in the remaining coding segment.
Mutations Made By	Paul Overbeek, Baylor College of Medicine

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

nephronophthisis 2

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

tetralogy of Fallot

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Developmental Biology Research
- Internal/Organ Defects
  - situs inversus
  - kidney
- Postnatal Lethality
Mouse/Human Gene Homologs
- situs inversus
Internal/Organ Research
- Kidney Defects
  - polycystic kidney disease

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Invs^inv/Invs^inv
involves: C57BL/6 * FVB/N

growth/size/body region phenotype

right-sided stomach
- at E18.5, 10 of 16 homozygotes display a right-sided stomach
- the sidedness of the aortic arch and stomach is concordant

left pulmonary isomerism
- at E18.5, 1 of 16 homozygotes displays left pulmonary isomerism

right pulmonary isomerism
- at E18.5, 3 of 16 homozygotes display right pulmonary isomerism

lung situs inversus
- at E18.5, >50% of homozygotes display a reversal of lung laterality resulting in a single-lobed right lung and a four-lobed left lung

respiratory system phenotype

left pulmonary isomerism
- at E18.5, 1 of 16 homozygotes displays left pulmonary isomerism

right pulmonary isomerism
- at E18.5, 3 of 16 homozygotes display right pulmonary isomerism

lung situs inversus
- at E18.5, >50% of homozygotes display a reversal of lung laterality resulting in a single-lobed right lung and a four-lobed left lung

cardiovascular system phenotype

dextrocardia
- at E18.5, the heart is malpositioned to the right

aorta hypoplasia
- at E18.5, 1 of 16 homozygotes displays a right-sided aortic arch with an underdeveloped aorta

double aortic arch
- at E18.5, 1 of 16 homozygotes displays a double aortic arch

right aortic arch
- at E18.5, most homozygotes (11 of 16) display a right-sided aortic arch

digestive/alimentary phenotype

right-sided stomach
- the sidedness of the aortic arch and stomach is concordant
- at E18.5, 10 of 16 homozygotes display a right-sided stomach

The following phenotype relates to a compound genotype created using this strain

Genotype: Invs^inv/Invs^inv
involves: FVB/N

cardiovascular system phenotype

abnormal direction of heart looping
- 6 of 8 have an inverted cardiac l-loop and the direction of looping is ambiguous in the other two

embryo phenotype

abnormal primitive node morphology
- aberrant cell masses are found around the node, which often deform the node shape and alter the positional arrangement of nodal cilia

abnormal direction of embryo turning
- direction of embryonic turning is reversed as the vitalline vessels are situated on the right size of the body

abnormal embryonic cilium location or orientation
- the positional arrangement of nodal cilia is often altered

abnormal motile primary cilium physiology
- although embryonic nodal cilia rotate as rapidly as those of wild-type embryos, the nodal flow is less smooth, much slower than normal, and more turbulent resulting in a slow net leftward transport in the node
- development of nodal flow arrests at nodal stage 3 or 4 and does not proceed to nodal stage 5

endocrine/exocrine gland phenotype

abnormal pancreatic islet morphology
- expansion and disorganization of the endocrine cells in the islets of Langerhans

dilated pancreatic duct
- dilation of the pancreatic ducts

pancreatic islet hyperplasia

abnormal pancreatic acinus morphology
- dilation of many of the acinar ducts

abnormal pancreatic acinar cell morphology
- vacuolization of the pancreatic acinar cells

decreased pancreatic acinar cell number
- decrease in the number of exocrine acinar cells

disorganized pancreatic islets

cellular phenotype

abnormal embryonic cilium location or orientation
- the positional arrangement of nodal cilia is often altered

abnormal motile primary cilium physiology
- although embryonic nodal cilia rotate as rapidly as those of wild-type embryos, the nodal flow is less smooth, much slower than normal, and more turbulent resulting in a slow net leftward transport in the node
- development of nodal flow arrests at nodal stage 3 or 4 and does not proceed to nodal stage 5

growth/size/body region phenotype

slow postnatal weight gain
- poor weight gain after P2

decreased body weight
- do not increase in weight after birth

situs inversus
- spleen and the apex of the heart found on the right side instead of the left
- 100% exhibit situs inversus, with stomach, spleen, heart, lungs, and liver being mirror-image left-right inversions

increased kidney weight
- at P7, cystic kidneys weigh more than twice as much as wild-type kidneys

decreased body size
- do not increase in size after birth

homeostasis/metabolism phenotype

increased blood urea nitrogen level
- 2-fold increase in blood urea nitrogen levels by P5

liver/biliary system phenotype

abnormal biliary tract morphology
- biliary obstruction or atresia

jaundice
- yellow discoloration of skin

mammalian phenotype

renal/urinary system phenotype
- Normal - normal-looking primary cilia (monocilia) are seen at apical surfaces of cystic collecting ducts and proximal tubules at P5
- Normal - in culture, primary mutant renal epithelial cells show no significant differences in the % of ciliated cells or in primary cilia length relative to wild-type controls
- Normal - primary mutant renal cilia exhibit normal bending mechanics in response to physiological fluid flow relative to wild-type cilia
- Normal - mutant proximal renal epithelial cells show a normal rise in intracellular Ca2+ concentration in response to fluid flow stress relative to wild-type cells

respiratory system phenotype
- Normal - normal 9 + 2 arrangement seen in respiratory cilia from trachea at P5

mortality/aging

postnatal lethality
- do not survive beyond 7 days of age
- usually die within the first week of life; one pup survived to P11

renal/urinary system phenotype

dilated kidney collecting duct
- within a couple of days after birth, kidneys are filled with severely dilated collecting ducts
- collecting ducts may appear haphazardly arranged in 2-D; however, 3-D imaging indicates that they maintain their parallel alignment from medulla to cortex
- fusiform dilatation of collecting ducts at P5
- cystic collecting ducts are uniformly and diffusely dilated throughout their entire lengths, except at the most proximal tips in the superficial cortex

dilated renal tubules
- soon after birth, tubules are severely dilated
- fusiform (not secular) dilatation of convoluted and straight proximal tubules, bridged by segments of normal or narrowed calibers at P3 and P5

kidney cysts
- more extensive, diffuse cortical and medullary cysts at P11
- cysts of increased size and number involving collecting ducts, proximal tubules and Bowman's spaces at P1
- relatively rapid development and progression of epithelial-lined renal cysts
- variously sized tubular cysts
- cysts first appear in collecting ducts and proximal tubules by E17
- expansion of Bowman's space surrounding deep cortical glomeruli already noted at E15

abnormal loop of Henle ascending limb thick segment morphology
- thick ascending limbs appear dilated

abnormal loop of Henle descending limb morphology
- some of these thin loops have diverticuli or flaring at their distal ends
- thin descending loops of Henle are narrowed at their transitions from S3 segments

kidney failure
- succumb to renal failure within 1 wk of life

kidney medulla cysts
- diffuse and elaborate medullary cysts noted at P11, more extensive than at P1

renal glomerulus cysts
- cystic dilatation of some glomeruli

abnormal kidney morphology
- significant kidney pathology with dilated tubules and abnormal glomeruli

dilated proximal convoluted tubules
- variable luminal widening and cyst formation at P5
- rare, small outpocketings seen along proximal tubules
- fusiform cysts, hairpin turns and narrowed segments in a single P4 convoluted proximal tubule

increased glomerular capsule space
- expansion of Bowman's space surrounding deep cortical glomeruli is first noted at E15 and persists through P11

abnormal kidney interstitium morphology
- relatively disorganized and more abundant interstitium at P5

kidney corticomedullary cysts
- corticomedullary cysts involving collecting ducts, proximal tubules, and thick ascending limbs at P5

abnormal kidney pelvis morphology
- defects in the organization of the pelvic region

increased kidney weight
- at P7, cystic kidneys weigh more than twice as much as wild-type kidneys

nephrocalcinosis
- dystrophic calcifications in less than 5% of tubular lumina by P11

proximal convoluted tubule brush border loss
- at P5, rarified microvilli resemble loose, ill-fitting pieces of jigsaw puzzles
- focal thinning of the apical brush border microvilli within progressively expanding cysts

abnormal renal glomerulus morphology

kidney cortex cysts
- diffuse and elaborate cortical cysts noted at P11, more extensive than at P1

digestive/alimentary phenotype

abnormal pancreatic acinus morphology
- dilation of many of the acinar ducts

dilated pancreatic duct
- dilation of the pancreatic ducts

abnormal pancreatic acinar cell morphology
- vacuolization of the pancreatic acinar cells

decreased pancreatic acinar cell number
- decrease in the number of exocrine acinar cells

Genotype: Invs^inv/Invs^inv
FVB/N-Invs

digestive/alimentary phenotype

abnormal intestine morphology
- 42.5% show incompletely inverted looping of the intestine, 35% show malrotation, and 20% almost complete inversion of the intestinal loop

right-sided stomach
- all have right-sided stomach, however the angle between the cardia and the pylorus of the stomach varies

endocrine/exocrine gland phenotype

abnormal pancreas morphology
- 68% have a warped pancreas which runs along the duodenal looping, but is almost normal in size, and the rest have severe hypoplasia of the pancreas

growth/size/body region phenotype

lung situs inversus
- 40% exhibit situs inversus of the lung and 50% show incomplete inversus

atrial situs inversus
- 85% exhibit atrial situs inversus, 7.5% with incomplete inversus, and 7.5% with left isomerism

left pulmonary isomerism
- 4 of 40 exhibit left isomerism of the lung, in which both sides of the lung are unilobed or pseudobilobed, and associated with hyparterial bronchi

left-sided isomerism

situs inversus
- each organ shows primary situs inversus with variable degrees of irregularity, ranging from almost complete form of situs inversus to left isomerism

abdominal situs ambiguus
- 20% exhibit abdominal heterotaxy, with an abdomen characterized by a symmetrical liver, hypoplastic spleen, small-lobed pancreas, and malrotation of the common gastrointestinal mesentery

left atrial isomerism
- 7.5% exhibit left atrial isomerism

right-sided stomach
- all have right-sided stomach, however the angle between the cardia and the pylorus of the stomach varies

situs ambiguus
- 25% show visceroatrial heterotaxy

hematopoietic system phenotype

abnormal spleen morphology
- 55% have normal sized spleen which is located along the great curvature of the right-sided stomach and 9% show a dysplastic spleen which is located bilaterally across the central line of the abdomen

spleen hypoplasia
- 22% have a hypoplastic spleen

immune system phenotype

abnormal spleen morphology
- 55% have normal sized spleen which is located along the great curvature of the right-sided stomach and 9% show a dysplastic spleen which is located bilaterally across the central line of the abdomen

spleen hypoplasia
- 22% have a hypoplastic spleen

liver/biliary system phenotype

abnormal liver morphology
- 35% show situs inversus of the liver, 20% have primary situs inversus with incomplete lobation, and 45% have left isomerism of the liver, in which the hepatic portion of the posterior vena cava is absent

respiratory system phenotype

lung situs inversus
- 40% exhibit situs inversus of the lung and 50% show incomplete inversus

left pulmonary isomerism
- 4 of 40 exhibit left isomerism of the lung, in which both sides of the lung are unilobed or pseudobilobed, and associated with hyparterial bronchi

cardiovascular system phenotype

abnormal vena cava morphology
- mutants sometimes exhibit posterior vena cava interruption

atrial situs inversus
- 85% exhibit atrial situs inversus, 7.5% with incomplete inversus, and 7.5% with left isomerism

double outlet right ventricle
- seen occasionally

abnormal atrioventricular cushion morphology
- mutants sometimes have an endocardial cushion defect

abnormal heart morphology
- mutants exhibit cardiovascular anomalies that are seen in various combinations
- 10% exhibit tetralogy of Fallot; seen in 20% of mutants with abdominal heterotaxy and 25% of mutants with visceroatrial heterotaxy

aortic valve stenosis
- mutants sometimes display aortic stenosis

transposition of great arteries
- seen occasionally

dextrocardia

left atrial isomerism
- 7.5% exhibit left atrial isomerism

Genotype: Invs^inv/Invs⁺
FVB/N-Invs

liver/biliary system phenotype

abnormal liver morphology
- often exhibit deformation of the inner left lobe of the liver, however display no cardiovascular abnormalities

References

Yokoyama T; Copeland NG; Jenkins NA; Montgomery CA; Elder FF; Overbeek PA. 1993. Reversal of left-right asymmetry: a situs inversus mutation [see comments] Science 260(5108):679-82PubMed: 8480178 MGI: J:4934

Additional - Invs^inv related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Separated MCA:Invs
- Genotyping resources and troubleshooting
Breeding Considerations

Homozygous mice die in the first week after birth. When maintaining a live colony, heterozygous mice may be bred to wildtype siblings or to FVB/NJ inbred mice.
- Additional Breeding and Husbandry Support
Citation
When using the inversion of embryonic turning mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #36523 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Terms Of Use

General Terms and Conditions

See MMRRC for Additional Conditions of Distribution

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:inversion of embryonic turning

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Invsinv

Allele Symbol: Invsinv

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Invsinv/Invsinvinvolves: C57BL/6 * FVB/N

growth/size/body region phenotype

respiratory system phenotype

cardiovascular system phenotype

digestive/alimentary phenotype

Genotype: Invsinv/Invsinvinvolves: FVB/N

cardiovascular system phenotype

embryo phenotype

endocrine/exocrine gland phenotype

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

mammalian phenotype

mortality/aging

renal/urinary system phenotype

digestive/alimentary phenotype

Genotype: Invsinv/InvsinvFVB/N-Invs

digestive/alimentary phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

hematopoietic system phenotype

immune system phenotype

liver/biliary system phenotype

respiratory system phenotype

cardiovascular system phenotype

Genotype: Invsinv/Invs+FVB/N-Invs

liver/biliary system phenotype

References

Additional - Invsinv related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Invs^inv

Allele Symbol: Invs^inv

Genotype: Invs^inv/Invs^inv
involves: C57BL/6 * FVB/N

Genotype: Invs^inv/Invs^inv
involves: FVB/N

Genotype: Invs^inv/Invs^inv
FVB/N-Invs

Genotype: Invs^inv/Invs⁺
FVB/N-Invs

Additional - Invs^inv related