Overview

Also Known As:Ihh KO

These Ihh knock-out mice exhibit embryonic lethality that may be due to circulatory abnormalities.

Donating Investigator

Andrew P McMahon, University of Southern California

Genetic overview

Genetic Background	Generation

Ihh^tm1Amc

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Ihh	Indian hedgehog

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Research Applications

Developmental Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Mice that are heterozygous for the targeted allele are viable and fertile. Mice homozygous for this mutation have a lethal phenotype. Half of homozygous null mice have an embryonic lethal phenotype, dying between 10.5 to 12.5 days post coitum. The cause of embryonic death may be due to circulatory abnormalities. Embryonic death also occurred in late gestation, with the remaining homozygous mutants dying at birth, due to respiratory failure. At 12.5 dpc, initial cartilaginous primordia of mutant embryos forelimbs are not abnormal, but by 13.5 dpc, mutant embryos display severe foreshortening of the forelimbs. At birth, the length of long bones of mutant animals are only one third the length of long bones of wildtype animals. Mutants have reduced chondrocyte proliferation, abnormal chondrocyte maturation and absence of mature osteoblasts in endochondral bones. Recent studies have linked mutations of Ihh to brachydactyly type A-1 St-Jacques. This mutant mouse strain represents a model that may be useful in studies of skeletal morphogenesis.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to replace the entire first exon, encoding much of the signaling peptide, and approximately 1kb of flanking sequence. The construct was electroporated into 129 derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 derived blastocysts. The resulting chimeric animals were backcrossed to 129X1 mice.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

St-Jacques B; Hammerschmidt M; McMahon AP. 1999. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation [published erratum appears in Genes Dev 1999 Oct 1;13(19):2617] Genes Dev 13(16):2072-86PubMed: 10465785 MGI: J:57297

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Genetics

Ihh^tm1Amc

Allele Symbol: Ihh^tm1Amc

Allele Name	targeted mutation 1, Andrew P McMahon
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Ihh^-; Ihhⁿ
Gene Symbol and Name	Ihh, Indian hedgehog
Gene Synonym(s)
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	1
Molecular Note	A neomycin resistance cassette replaced the entire first exon, which encodes much of the signaling peptide, and approximately 1kb of flanking sequence.
Mutations Made By	Andrew McMahon, University of Southern California

Disease/Phenotype

Disease Terms

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).

Hirschsprung's disease

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

annular pancreas

Research Areas By Phenotype

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

Genotype: Ihh^tm1Amc related

Developmental Biology Research
- Embryonic Lethality (Homozygous)
  - incomplete
- Perinatal Lethality
  - Homozygous

Mammalian Phenotype Terms by Genotype

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

Genotype: Ihh^tm1Amc/Ihh^tm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

cardiovascular system phenotype

abnormal vitelline vasculature morphology
- yolk sacs have fewer and thinner blood vessels compared to wild-type at E9.5

embryo phenotype

abnormal visceral yolk sac morphology

abnormal vitelline vasculature morphology
- yolk sacs have fewer and thinner blood vessels compared to wild-type at E9.5

Genotype: Ihh^tm1Amc/Ihh^tm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J

endocrine/exocrine gland phenotype

annular pancreas
- at 18.5 dpc, 43% of homozygotes exhibit an annular pancreas

growth/size/body region phenotype

decreased fetal size
- at 18.5 dpc, mutant embryos have an overall reduced size relative to wild-type embryos

mammalian phenotype

digestive/alimentary phenotype
- Normal - at 18.5 dpc, homozygotes exhibit no intestinal transformation of the stomach epithelium

muscle phenotype

abnormal smooth muscle morphology
- at 18.5 dpc, homozygotes show a 34% reduction in thickness of the circular smooth muscle layer along the small intestine

nervous system phenotype

absent enteric neurons
- at 18.5 dpc, enteric neurons are completely absent along parts of the small intestine and in dilated portions of the colon

digestive/alimentary phenotype

abnormal small intestine morphology
- at 18.5 dpc, homozygotes show a 34% reduction in thickness of the circular smooth muscle layer along the small intestine
- at 18.5 dpc, homozygotes show a significant dilation of the small intestine
- at this stage, the size of mutant villi is markedly reduced concomitant with a 54% decrease in epithelial stem cell proliferation between and at the base of villi

abnormal duodenum morphology
- at 18.5 dpc, no duodenal stenosis is observed
- at 18.5 dpc, homozygotes show a 45% reduction in the number of cholecystokinin-producing cells of the duodenum

megacolon
- at 18.5 dpc, homozygotes display a significant dilation of parts of the colon as well as a thin wall

aganglionic megacolon
- at 18.5 dpc, 50% of homozygotes display an aganglionic megacolon

abnormal digestive organ placement
- at 18.5 dpc, all homozygotes display an obvious malrotation of the gut, in the absence of reversions in gut situs

abnormal digestive system morphology
- at 18.5 dpc, homozygotes display a smaller gastrointestinal tract relative to wild-type

Genotype: Ihh^tm1Amc/Ihh⁺
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

skeleton phenotype

decreased long bone epiphyseal plate size
- modest shortening of the growth plate

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

Genotype: Ihh^tm1Amc/Ihh^tm1Amc
involves: 129S1/Sv * 129X1/SvJ

cellular phenotype

decreased chondrocyte proliferation
- decrease in chondrocyte proliferation at E14.5

limbs/digits/tail phenotype

short limbs
- at 13.5 dpc, homozygotes display visibly shortened forelimbs
- at birth, homozygotes display significant dwarfism of the limbs
- 60-80% reduction in the length of the stylopod and the zeugopod at birth

abnormal digit morphology
- failure of digit segmentation and ossification
- homozygotes display failure of digit segmentation: at 18.5 dpc, mutant digits remain unsegmented and uncalcified

short fibula

short tail

abnormal forelimb morphology
- at 13.5 dpc, homozygotes display visibly shortened forelimbs

abnormal humerus morphology
- at 18.5 dpc, the mutant humerus and ulna remain partly fused
- at 18.5 dpc, mutant humeri display no identifiable cortical bone, even in vascularized areas of the perichondrium

short humerus

short tibia
- growth retardation of tibia

short ulna

fused carpal bones
- at 18.5 dpc, some of the wrist bones of homozygotes appear partly fused

mammalian phenotype

vision/eye phenotype
- Normal - astrocyte precursor cells at the optic disc and in the optic nerve develop normally
- Normal - no rosettes are observed in the retina

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance
- some lethality also occurs at later stages of gestation
- about 50% of homozygotes die at midgestation between 10.5 and 12.5 dpc, probably as a result of circulatory defects

neonatal lethality, complete penetrance
- homozygotes that develop to term die at birth due to respiratory failure

respiratory system phenotype

respiratory failure

skeleton phenotype

abnormal humerus morphology
- at 18.5 dpc, mutant humeri display no identifiable cortical bone, even in vascularized areas of the perichondrium
- at 18.5 dpc, the mutant humerus and ulna remain partly fused

abnormal long bone epiphyseal plate proliferative zone
- as early as 12.5 dpc, mutant humeri show a ~50% reduction in chondrocyte proliferation; in addition, the length of proliferative zone is severely reduced

decreased length of long bones
- at birth, mutant long bones are one-third the length of wild-type long bones

short scapula
- length of scapula is shorter

abnormal bone mineralization
- by 18.5 dpc, ectopic calcification extends closer to the articular surfaces in mutant bones, including the humerus, sternum, vertebrae, and cartilaginous synchondroses of the base of the skull
- at 16.5 dpc, mutant humeri show ectopic initial calcification in the center of cartilage only, suggesting that mineralization occurs in cartilage and not in association with a bone collar

abnormal rib morphology
- mutant ribs do not display excessive calcification

abnormal trabecular bone morphology
- 18.5 dpc, mutant humeri display no identifiable trabecular bone in the primary spongiosa

delayed endochondral bone ossification
- in homozygous newborns, most endochondral bones are shorter and relatively malformed
- homozygotes exhibit absence of endochondral bone formation prior to birth

short humerus

short ribs
- homozygotes have significantly shortened ribs

abnormal bone ossification
- in homozygotes, appendicular skeletal elements fail to ossify

decreased osteoblast cell number
- in contrast, mature osteoblasts are present in mutant bones formed by intramembranous ossification (e.g. flat bones of the skull, mandible, and clavicle)
- at 18.5 dpc, homozygotes show no osteocalcin expression in endochondral bones of the appendicular or axial skeleton, indicating absence of mature osteoblasts in mutant long bones

decreased width of hypertrophic chondrocyte zone
- at 13.5 dpc, mutant humeri show absence of typical hypertrophic chondrocytes
- at 14.5 dpc, some hypertrophic cells are found in the center of mutant humeri but are neither as large nor as well-organized as those of wild-type bones
- such hypertrophic cells are surrounded by less mature chondrocytes and show no signs of vascularization or cortical bone formation

short mandible
- at birth, homozygotes display a foreshortened mandible

abnormal chondrocyte differentiation
- homozygotes display ectopic maturation of chondrocytes: chondrocyte differentiation is initially delayed, but when it occurs, hypertrophic cells fail to exhibit a stacked columnar organization and occupy inappropriate positions close to articular surfaces
- premature chondrocyte hypertrophy, resulting in depletion of non-mineralized cartilage at articular ends of long bones

chondrodystrophy
- reduced chondrocyte proliferation and severe short-limb dwarfism are seen

decreased chondrocyte proliferation
- decrease in chondrocyte proliferation at E14.5

abnormal long bone morphology
- depletion of non-mineralized cartilage at articular ends of long bones
- mutant long bones fail to show any signs of calcification at 14.5 dpc, as expected; instead, calcification is first noted at 16.5 dpc in mutant scapula and humerus, and slightly later in radius and ulna

domed cranium
- at birth, homozygotes show a rounded skull

short fibula

abnormal axial skeleton morphology

short ulna

abnormal skeleton morphology
- in homozygotes, most skeletal elements are present in the right position and in the right number; however, all elements of the axial and appendicular skeletons exhibit dwarfism

short tibia
- growth retardation of tibia

abnormal cartilage development
- although initial cartilage elements develop normally, 13.5-dpc mutant forelimbs show a slight reduction in each cartilage element relative to wild-type; this size difference is clearly visible at 14.5 dpc

abnormal joint morphology
- at 18.5 dpc, homozygotes show abnormal joint formation

abnormal skeleton development
- skeletal growth retardation

fused carpal bones
- at 18.5 dpc, some of the wrist bones of homozygotes appear partly fused

craniofacial phenotype

short snout
- at birth, homozygotes show a foreshortened snout

domed cranium
- at birth, homozygotes show a rounded skull

short mandible
- at birth, homozygotes display a foreshortened mandible

growth/size/body region phenotype

short snout
- at birth, homozygotes show a foreshortened snout

disproportionate dwarf
- at birth mutants display severe short-limb dwarfism

decreased body height
- at birth, homozygotes are consistently shorter than wild-type mice

References

St-Jacques B; Hammerschmidt M; McMahon AP. 1999. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation [published erratum appears in Genes Dev 1999 Oct 1;13(19):2617] Genes Dev 13(16):2072-86PubMed: 10465785 MGI: J:57297

Additional - Ihh^tm1Amc related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Ihh
- Genotyping resources and troubleshooting
Breeding Considerations

This strain originated and is maintained on a 129 background. The strain is maintained by heterozygous intercrosses. Homozygous lethal.
- Additional Breeding and Husbandry Support
Citation
When using the Ihh KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #004290 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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or Wild-type for Ihh<tm1Amc>

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Use of MICE by companies or for-profit entities requires a license prior to shipping.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:Ihh KO

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Ihhtm1Amc

Allele Symbol: Ihhtm1Amc

Disease Terms

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).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

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

Genotype: Ihhtm1Amc related

Mammalian Phenotype Terms by Genotype

Genotype: Ihhtm1Amc/Ihhtm1Amcinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6

cardiovascular system phenotype

embryo phenotype

Genotype: Ihhtm1Amc/Ihhtm1Amcinvolves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J

endocrine/exocrine gland phenotype

growth/size/body region phenotype

mammalian phenotype

muscle phenotype

nervous system phenotype

digestive/alimentary phenotype

Genotype: Ihhtm1Amc/Ihh+involves: 129S1/Sv * 129X1/SvJ * C57BL/6

skeleton phenotype

Genotype: Ihhtm1Amc/Ihhtm1Amcinvolves: 129S1/Sv * 129X1/SvJ

cellular phenotype

limbs/digits/tail phenotype

mammalian phenotype

mortality/aging

respiratory system phenotype

skeleton phenotype

craniofacial phenotype

growth/size/body region phenotype

References

Additional - Ihhtm1Amc related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

Ihh^tm1Amc

Allele Symbol: Ihh^tm1Amc

Genotype: Ihh^tm1Amc related

Genotype: Ihh^tm1Amc/Ihh^tm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Genotype: Ihh^tm1Amc/Ihh^tm1Amc
involves: 129S1/Sv * 129X1/SvJ * C57BL/6J * CBA/J

Genotype: Ihh^tm1Amc/Ihh⁺
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Genotype: Ihh^tm1Amc/Ihh^tm1Amc
involves: 129S1/Sv * 129X1/SvJ

Additional - Ihh^tm1Amc related