Overview

Homozygous Ednra (endothelin receptor type A) targeted mutant embryos are born with numerous defects in craniofacial structures. Defects also exist in the heart, including double outlet right ventricle, transposition of the great arteries, interruption of the aorta and persistent truncus arteriosus.

Donating Investigator

Dr. Masashi Yanagisawa, Southwestern Medical School

Genetic overview

Genetic Background	Generation

Ednra^tm1Ywa

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Ednra	endothelin receptor type A

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Research Applications

Developmental Biology Research

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Details

Detailed Description

Homozygous endothelin receptor type A targeted mutant embryos are born with numerous defects in craniofacial structures. The mandible appears to have undergone a homeotic transformation into a maxilla. Other maxillary structures are duplicated in the lower jaw, including the palatine, jugal and pterygoid bones. The malleus and incus of the middle ear are dysmorphic and Meckel's cartilage is absent. The hyoid bone of the throat is moved rostrally and fused with the pterygoid bones, resulting in collapse of the trachea and subsequent asphyxia. Defects also exist in the heart, including double outlet right ventricle, transposition of the great arteries, interruption of the aorta and persistent truncus arteriosus. While all mutant mice have cardiac defects, the specific type of defect differs between embryos. Expression of the targeted gene (total embryo RNA) is still observed in homozygous mutant embryos, though there is a shift in size, suggestive of a partial mRNA. Ligand binding assays confirm that no functional receptor is present in the mutant embryos, however.

Development

Exons 5 and 6 of the targeted gene, corresponding to the sixth and seventh transmembrane domains, were replaced with a neomycin resistance cassette driven by the RNA polymerase II promoter. The targeting construct was electroporated into 129S7/SvEvBrd-derived JH1 embryonic stem (ES) cells. Correctly targeted ES cell clones were injected into C57BL/6 blastocysts. Mice were bred to 129S6/SvEvTac mice.

Selected References

Clouthier DE; Hosoda K; Richardson JA; Williams SC; Yanagisawa H; Kuwaki T; Kumada M; Hammer RE; Yanagisawa M. 1998. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125(5):813-24PubMed: 9449664 MGI: J:46639

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Genetics

Ednra^tm1Ywa

Allele Symbol: Ednra^tm1Ywa

Allele Name	targeted mutation 1, Masashi Yanagisawa
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	ET/A -
Gene Symbol and Name	Ednra, endothelin receptor type A
Gene Synonym(s)
Strain of Origin	129S7/SvEvBrd
Chromosome	8
Molecular Note	A neomycin selection cassette replaced a genomic fragment containing exons 5 and 6, which encode the sixth and seventh transmembrane domains of the protein. Radioligand binding assays on samples derived from skin of homozygous embryos demonstrated that no functional protein was produced from this allele.
Mutations Made By	Dr. Masashi Yanagisawa, Southwestern Medical School

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).

velocardiofacial syndrome

Research Areas By Phenotype

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

Developmental Biology Research
- Internal/Organ Defects
  - heart: vasculature
  - heart
- Craniofacial and Palate Defects
- Postnatal 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: Ednra^tm1Ywa/Ednra^tm1Ywa
involves: 129S7/SvEvBrd

growth/size/body region phenotype

abnormal mouth floor morphology
- palatal rugae are abnormally present on the floor of the mouth

hearing/vestibular/ear phenotype

absent gonial bone

absent tympanic ring

skeleton phenotype

abnormal mandible morphology
- the mandible appears to be a mirror image duplicate of the maxilla complete with formina and palatine bones
- the lower jaw is shortened and covered with soft tissue resembling the soft tissue of the snout
- the mandible is flattened and abnormally attached to the jugal bone by a bone that appears to be a mirror image duplicate of the jugal bone

abnormal palatine bone morphology
- both the original and duplicate palatine bones are smaller than normal

lower jaw to upper jaw transformation
- the mandible appears to be a mirror image duplicate of the maxilla complete with formina and palatine bones

small zygomatic bone
- both the zugal bone and its mirror image duplicate are smaller than the normal jugal bone and form an abnormal joint

abnormal Meckel's cartilage morphology
- the body of the Meckel's cartilage is absent and at E14.5 the rostral process is hypoplastic

absent gonial bone

abnormal maxilla morphology
- the incisors are present but set in only a small amount of alveolar bone and residual cartilage

abnormal alisphenoid bone morphology
- the alisphenoid bones are duplicated

craniofacial phenotype

abnormal maxilla morphology
- the incisors are present but set in only a small amount of alveolar bone and residual cartilage

lower jaw to upper jaw transformation
- the mandible appears to be a mirror image duplicate of the maxilla complete with formina and palatine bones

abnormal mandible morphology
- the lower jaw is shortened and covered with soft tissue resembling the soft tissue of the snout
- the mandible appears to be a mirror image duplicate of the maxilla complete with formina and palatine bones
- the mandible is flattened and abnormally attached to the jugal bone by a bone that appears to be a mirror image duplicate of the jugal bone

abnormal Meckel's cartilage morphology
- the body of the Meckel's cartilage is absent and at E14.5 the rostral process is hypoplastic

small zygomatic bone
- both the zugal bone and its mirror image duplicate are smaller than the normal jugal bone and form an abnormal joint

absent gonial bone

abnormal palatine bone morphology
- both the original and duplicate palatine bones are smaller than normal

abnormal alisphenoid bone morphology
- the alisphenoid bones are duplicated

abnormal mouth floor morphology
- palatal rugae are abnormally present on the floor of the mouth

Genotype: Ednra^tm1Ywa/Ednra^tm1Ywa
involves: 129S7/SvEvBrd * C57BL/6 * CBA

cardiovascular system phenotype

abnormal third pharyngeal arch artery morphology
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
- at E12.5 the external carotid fails to branch off of arch arteries 3
- at E12.5 arch arteries 3 become the dominant vessels bilaterally, accepting blood from the outflow tract
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- at E12.0 - 12.5 right arch artery 3 is markedly enlarged in 2 out of 6 embryos
- at E12.5 the overall growth of arch arteries 3 toward the cranial direction is delayed

abnormal fourth pharyngeal arch artery morphology
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
- between E11.5 and E13.5 the fourth arch arteries are diminished
- at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 4 shows signs of regression including decreased diameter and expression of a transgenic lacZ marker of arterial smooth muscle (4 out of 6 and 2 out of 5, respectively)
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)

abnormal sixth pharyngeal arch artery morphology
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6

double outlet right ventricle

persistent right dorsal aorta
- at E12.0 - 12.5 and E13.0 - 13.5 the right dorsal aorta remains (5 out of 6 and 5 out of 5)
- in term embryos with abnormal regression of right arch artery 4 and normal regression of the right ductus caroticus, the right dorsal aorta persists and the right subclavian artery is missing or originates from the dorsal aorta
- at E13.0 the connection of the right dorsal aorta to the abdominal dorsal aorta persists

aberrant origin of the right subclavian artery
- in term embryos with abnormal regression of right arch artery 4 and normal regression of the right ductus caroticus, the right dorsal aorta persists and the right subclavian artery is missing or originates from the dorsal aorta
- the right subclavian artery is missing or has a cervical origin in term embryos as a result of abnormal regression of right arch artery 4

abnormal artery morphology
- the branchial arch artery patterning abnormalities result in various types of great vessel malformations

persistent right 6th pharyngeal arch artery
- at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 6 abnormally persists (4 out of 6 and 3 out of 5)
- at E13.0 in embryos where the right arch artery 4 regressed the right arch artery 6 persisted

persistent truncus arteriosis

abnormal ascending aorta morphology
- at E13.0 some embryos have extra branches from the ascending aorta

abnormal pharyngeal arch artery morphology
- at E12.5 both right and left ductus caroticus remain in 100% and 83% of embryos respectively

double aortic arch
- double aortic arch is found in term embryos when both the right and left arch arteries 4 abnormally regress or when left arch artery 6 abnormally regresses

overriding aortic valve
- other outflow tract abnormalities such as overriding aorta, double outlet right ventricle, and persistent truncus arteriosus are observed

craniofacial phenotype

abnormal fourth pharyngeal arch artery morphology
- at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 4 shows signs of regression including decreased diameter and expression of a transgenic lacZ marker of arterial smooth muscle (4 out of 6 and 2 out of 5, respectively)
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
- between E11.5 and E13.5 the fourth arch arteries are diminished

abnormal pharyngeal arch artery morphology
- at E12.5 both right and left ductus caroticus remain in 100% and 83% of embryos respectively

abnormal third pharyngeal arch artery morphology
- at E12.5 the overall growth of arch arteries 3 toward the cranial direction is delayed
- at E12.0 - 12.5 right arch artery 3 is markedly enlarged in 2 out of 6 embryos
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
- at E12.5 arch arteries 3 become the dominant vessels bilaterally, accepting blood from the outflow tract
- at E12.5 the external carotid fails to branch off of arch arteries 3
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)

persistent right 6th pharyngeal arch artery
- at E13.0 in embryos where the right arch artery 4 regressed the right arch artery 6 persisted
- at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 6 abnormally persists (4 out of 6 and 3 out of 5)

abnormal sixth pharyngeal arch artery morphology
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6

embryo phenotype

abnormal third pharyngeal arch artery morphology
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- at E12.5 the external carotid fails to branch off of arch arteries 3
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
- at E12.5 arch arteries 3 become the dominant vessels bilaterally, accepting blood from the outflow tract
- at E12.0 - 12.5 right arch artery 3 is markedly enlarged in 2 out of 6 embryos
- at E12.5 the overall growth of arch arteries 3 toward the cranial direction is delayed

abnormal fourth pharyngeal arch artery morphology
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6
- between E11.5 and E13.5 the fourth arch arteries are diminished
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 4 shows signs of regression including decreased diameter and expression of a transgenic lacZ marker of arterial smooth muscle (4 out of 6 and 2 out of 5, respectively)

abnormal sixth pharyngeal arch artery morphology
- this occurred more frequently on the right side (6 out of 8 than on the left 3 out of 8)
- in E11.5 embryos 50% (2/4) show enlargement of right arch artery 3 and relative narrowing of arch arteries 4 and 6

persistent right 6th pharyngeal arch artery
- at E12.0 - 12.5 and E13.0 - 13.5 right arch artery 6 abnormally persists (4 out of 6 and 3 out of 5)
- at E13.0 in embryos where the right arch artery 4 regressed the right arch artery 6 persisted

abnormal pharyngeal arch artery morphology
- at E12.5 both right and left ductus caroticus remain in 100% and 83% of embryos respectively

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

Genotype: Ednra^tm1Ywa/Ednra^tm1Ywa
129S/SvEv-Ednra

cellular phenotype

patent ductus arteriosus
- aortic interruption results in a dominant ductus arterious that subsequently joins the dorsal aorta

craniofacial phenotype

abnormal first pharyngeal arch morphology
- electron microscopy at E10.5 revealed poor swelling of the mandibular arch
- mandibular arch explants from E9.5 embryos showed poor development of the tongue epithelium, teeth, and glandular tissue

mandible hypoplasia
- membranous bone extends ventrocaudally forming a sheet-like structure that is fused to the endochondral bone
- at E18.5 the mandible is hypoplastic, highly disorganized and abnormally articulated

small zygomatic bone
- the jugal bone is smaller and its articulation with the mandible is abnormal

cleft chin
- at E18.5 the mandible in some lacked fusion at the midline

abnormal mouth morphology

abnormal palatine bone morphology
- the palatine bone is underdeveloped

abnormal palate morphology
- thickening of the palate, essentially preventing oral respiration
- fusion of the soft palate to the lateral floor of the oral cavity proximal to the squamous/respiratory epithelial boundary

absent Meckel's cartilage
- at E14.5 Meckel's cartilage is absent

abnormal middle ear ossicle morphology
- abnormalities are found in the neural crest derived structures of the middle ear in 100% of embryos at E18.5

abnormal styloid process morphology
- the cartilaginous anlage of the styloid process is absent

absent incus

absent malleus

absent stapes
- the cartilaginous rudiment of the stapes is absent in 11 out of 14 embryos

small second pharyngeal arch
- at E10.5, the second arch is relatively small

tongue hypoplasia
- at E18.5 the tongue and associated muscles are severely hypoplastic

abnormal outer ear morphology
- at E18.5 the auricles are hypoplastic (14 out of 14)

digestive/alimentary phenotype

abnormal palate morphology
- thickening of the palate, essentially preventing oral respiration
- fusion of the soft palate to the lateral floor of the oral cavity proximal to the squamous/respiratory epithelial boundary

absent salivary gland
- at E18.5 many of the mandibular salivary glands and the submandibular glands are missing

tongue hypoplasia
- at E18.5 the tongue and associated muscles are severely hypoplastic

absent submandibular gland
- at E18.5

embryo phenotype

abnormal first pharyngeal arch morphology
- electron microscopy at E10.5 revealed poor swelling of the mandibular arch
- mandibular arch explants from E9.5 embryos showed poor development of the tongue epithelium, teeth, and glandular tissue

small second pharyngeal arch
- at E10.5, the second arch is relatively small

endocrine/exocrine gland phenotype

thymus hypoplasia
- the thymus is hypoplastic and rostrally displaced (14 out of 14)

ectopic thymus
- the thymus is hypoplastic and rostrally displaced (14 out of 14)

absent salivary gland
- at E18.5 many of the mandibular salivary glands and the submandibular glands are missing

absent submandibular gland
- at E18.5

growth/size/body region phenotype

abnormal mouth morphology

abnormal palate morphology
- fusion of the soft palate to the lateral floor of the oral cavity proximal to the squamous/respiratory epithelial boundary
- thickening of the palate, essentially preventing oral respiration

abnormal outer ear morphology
- at E18.5 the auricles are hypoplastic (14 out of 14)

tongue hypoplasia
- at E18.5 the tongue and associated muscles are severely hypoplastic

cleft chin
- at E18.5 the mandible in some lacked fusion at the midline

cardiovascular system phenotype

aorta tubular hypoplasia
- tubular hypoplasia of the aorta occurred in 9 out of 16 pups

interrupted aorta
- interruption of the aorta occurs in 7 out of 16 pups

perimembraneous ventricular septal defect
- ventricular septal defects are found in 92% (23 out of 25) of mutant embryos at E18.5

absent right subclavian artery
- absence of the right subclavian artery occurred in 4 out of 9 pups

overriding aortic valve
- the aorta overrides the crest of the ventricular septum in 11 out 25 pups

transposition of great arteries
- 13% (2/16) show complete transposition of the great arteries

abnormal dorsal aorta morphology

abnormal cardiovascular system morphology
- the cumulative penetrance of outflow tract abnormalities is 100% however the type of abnormality varied

abnormal carotid artery morphology
- extra small arteries branching off the carotid arteries are found in 2 out of 9 pups

double outlet right ventricle
- the aorta arises from the right ventricle resulting in double outlet right ventricle (7 out of 25)

persistent truncus arteriosis
- 6% (1/16) show persistant truncus arteriosus

patent ductus arteriosus
- aortic interruption results in a dominant ductus arterious that subsequently joins the dorsal aorta

hearing/vestibular/ear phenotype

abnormal outer ear morphology
- at E18.5 the auricles are hypoplastic (14 out of 14)

absent malleus

abnormal middle ear ossicle morphology
- abnormalities are found in the neural crest derived structures of the middle ear in 100% of embryos at E18.5

absent incus

absent tubotympanic recess
- the tubotympanic recess is absent resulting in the absence of the tympanic membrane

absent stapes
- the cartilaginous rudiment of the stapes is absent in 11 out of 14 embryos

absent tympanic membrane

absent tympanic ring

hematopoietic system phenotype

ectopic thymus
- the thymus is hypoplastic and rostrally displaced (14 out of 14)

thymus hypoplasia
- the thymus is hypoplastic and rostrally displaced (14 out of 14)

immune system phenotype

thymus hypoplasia
- the thymus is hypoplastic and rostrally displaced (14 out of 14)

ectopic thymus
- the thymus is hypoplastic and rostrally displaced (14 out of 14)

mortality/aging

perinatal lethality, complete penetrance
- all respond poorly to tapping and pinching stimuli
- none of the homozygotes opened their mouths to breath

muscle phenotype

abnormal muscle morphology
- at E18.5 the muscles and connective tissue in the anterior neck are poorly developed

nervous system phenotype

abnormal mandibular nerve branching
- the mandibular branch of the trigeminal nerve fails to project to the most distal aspects of the arches at E10.5 and E11.5
- ectopic fiber growth is seen on the mandibular branch of the trigeminal nerve at E11.5

abnormal facial nerve morphology
- the facial nerve fails to project to the most distal aspects of the arches at E10.5 and E11.5
- ectopic fiber growth is seen on the facial nerve at E11.5

abnormal trigeminal nerve morphology
- the maxillary branch of the trigeminal nerve shows decreased arborization within the frontonasal region at E11.5

respiratory system phenotype

abnormal pulmonary ventilation
- ps
- after tracheostomy to relieve mechanical asphyxia, mutant pups respond to exposure to hypoxic gas with a significant decrease in ventilatory response, in contrast under the same conditions there was a significant increase in ventilatory response in wild-type pups
- ype pups
- after tracheostomy to relieve mechanical asphyxia, mutant pups respond to exposure to hypercapnic gas with a slight decrease in ventilatory response, in contrast under the same conditions there was a marked increase in ventilatory response in wild-type pups

skeleton phenotype

absent incus

absent Meckel's cartilage
- at E14.5 Meckel's cartilage is absent

abnormal skeleton morphology
- at E18.5 fusion occurs between the lesser horns of the hyoid bone and an area encompassing the basiphenoid bone, the pterygoid bones and the ala temporalis cartilage
- the ventral neck is sunken
- at E14.5 the cartilangenous rudiment of the hyoid bone is moved ventrorostrally and fused to a cartilaginous precursor of a cranial bone

mandible hypoplasia
- at E18.5 the mandible is hypoplastic, highly disorganized and abnormally articulated
- membranous bone extends ventrocaudally forming a sheet-like structure that is fused to the endochondral bone

abnormal palatine bone morphology
- the palatine bone is underdeveloped

abnormal styloid process morphology
- the cartilaginous anlage of the styloid process is absent

abnormal middle ear ossicle morphology
- abnormalities are found in the neural crest derived structures of the middle ear in 100% of embryos at E18.5

absent malleus

absent stapes
- the cartilaginous rudiment of the stapes is absent in 11 out of 14 embryos

small zygomatic bone
- the jugal bone is smaller and its articulation with the mandible is abnormal

cleft chin
- at E18.5 the mandible in some lacked fusion at the midline

References

Clouthier DE; Hosoda K; Richardson JA; Williams SC; Yanagisawa H; Kuwaki T; Kumada M; Hammer RE; Yanagisawa M. 1998. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development 125(5):813-24PubMed: 9449664 MGI: J:46639

Additional - Ednra^tm1Ywa related

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Breeding Considerations

When maintained as a live colony, heterozygotes may be bred. Homozygotes are neonatal lethal, dying from mechanical asphyxia at birth.
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Citation
When using the 129S-Ednra^tm1Ywa/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #008865 in your Materials and Methods section.

Animal Health Reports

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

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	Heterozygous or wild-type for Ednra<tm1Ywa>

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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.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Selected References

Ednratm1Ywa

Allele Symbol: Ednratm1Ywa

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).

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Ednratm1Ywa/Ednratm1Ywainvolves: 129S7/SvEvBrd

growth/size/body region phenotype

hearing/vestibular/ear phenotype

skeleton phenotype

craniofacial phenotype

Genotype: Ednratm1Ywa/Ednratm1Ywainvolves: 129S7/SvEvBrd * C57BL/6 * CBA

cardiovascular system phenotype

craniofacial phenotype

embryo phenotype

Genotype: Ednratm1Ywa/Ednratm1Ywa129S/SvEv-Ednra

cellular phenotype

craniofacial phenotype

digestive/alimentary phenotype

embryo phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

cardiovascular system phenotype

hearing/vestibular/ear phenotype

hematopoietic system phenotype

immune system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

respiratory system phenotype

skeleton phenotype

References

Additional - Ednratm1Ywa 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

Ednra^tm1Ywa

Allele Symbol: Ednra^tm1Ywa

Genotype: Ednra^tm1Ywa/Ednra^tm1Ywa
involves: 129S7/SvEvBrd

Genotype: Ednra^tm1Ywa/Ednra^tm1Ywa
involves: 129S7/SvEvBrd * C57BL/6 * CBA

Genotype: Ednra^tm1Ywa/Ednra^tm1Ywa
129S/SvEv-Ednra

Additional - Ednra^tm1Ywa related