Overview

Homozygous Isl1 (ISL1 transcription factor, LIM/homeodomain) targeted mutation embryos are arrested in their development soon after embryonic day 9.5 (E9.5) and demonstrate abnormalities in the organization of the vascular endothelium and its surrounding mesenchyme. Motor neurons are not generated without ISL1 protein and a population of interneurons that express engrailed 1 (EN1) also fails to differentiate in these mutant embryos.

Donating Investigator

Samuel L Pfaff, The Salk Institute

Genetic overview

Genetic Background	Generation

Isl1^tm1Tmj

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Isl1	ISL1 transcription factor, LIM/homeodomain

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Research Applications

Neurobiology Research
Developmental Biology Research

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Details

Detailed Description

Homozygous embryos are arrested in their development soon after embryonic day 9.5 (E9.5) but exhibit an overtly normal organization of neural, mesodermal, and endodermal tissues. Histological analysis of embryos reveals abnormalities in the organization of the vascular endothelium and its surrounding mesenchyme, notably a disruption in the formation of the dorsal aorta. An impairment in vascular development is therefore a possible cause of the embryonic lethality in homozygous mutants. Motor neurons are not generated without ISL1 protein, although many other aspects of cell differentiation in the neural tube occur normally. A population of interneurons that express engrailed 1 (EN1), however, also fails to differentiate in these mutant embryos. ISL1 is required for the generation of motor neurons and motor neuron generation is required for the subsequent differentiation of certain interneurons.

Homozygote embryos analyzed at E9.5 express a modified transcript in mesodermal cells, but no expression is detected in neural tissues. No ISL1 immunoreactivity is detected in any tissues in homozygous mutant embryos, indicating that the targeted mutation eliminates expression of ISL1 protein.

Development

Exon 3 (LIM domain 2) of the gene was replaced by a neomycin resistance cassette. The targeting vector was electroporated into 129S1/Sv Oca2⁺ Tyr⁺ Kitl ⁺-derived W9.5/W95 embryonic stem (ES) cells. The line was initially backcrossed to C57BL/6 and then to CB6F1/J mice for 12 years by the donating laboratory.

Selected References

Pfaff SL; Mendelsohn M; Stewart CL; Edlund T; Jessell TM. 1996. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84(2):309-20PubMed: 8565076 MGI: J:31131

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Genetics

Isl1^tm1Tmj

Allele Symbol: Isl1^tm1Tmj

Allele Name	targeted mutation 1, Thomas M Jessell
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Isl1^tm1Tmj; targeted mutation 1, Thomas M Jessell
Gene Symbol and Name	Isl1, ISL1 transcription factor, LIM/homeodomain
Gene Synonym(s)	Isl-1; isl-1=homeobox; Islet 1; ISLET1
Strain of Origin	129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺
Chromosome	13
Molecular Note	A neomycin selection cassette was inserted such that the exon encoding the second LIM domain was deleted and that splicing from the exon encoding the first LIM domain to the exon encoding the homeodomain would result in a frameshift mutation. In situ hybridization did not detect transcript produced from this allele in the neural tube of homzygous mutant mice, but message was detected in the mesoderm ventral to the neural tube. Immunohistochemical analysis of homozygous mutant embryonic sections showed a lack of protein in all analyzed tissues.
Mutations Made By	Thomas Jessell, Columbia University/HHMI

Disease/Phenotype

Disease Terms

Research Areas By Genotype

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

Neurobiology Research
- Neurodevelopmental Defects
Developmental Biology Research
- Embryonic 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: Isl1^tm1Tmj/Isl1^tm1Tmj
either: 129S1/Sv-Isl1 or (involves: 129S1/Sv * C57BL/6J)

cardiovascular system phenotype

abnormal dorsal aorta morphology
- dorsal aorta formation is disrupted at E9.5-10.5

abnormal vascular endothelial cell morphology
- exhibit abnormalities in the organization of the vascular endothelium and its surrounding mesenchyme at E9.5-10.5

nervous system phenotype

abnormal motor neuron morphology
- exhibit a marked increase in the incidence of apoptotic cell death in the ventral neural tube, the region in which motor neurons normally are generated
- exhibit an approximately 73% decrease in mitotic cells in the ventral neural tube, indicating decreased cell proliferation of cells that give rise to motor neurons
- isolated neural tube segments do not generate motor neurons in culture, indicating an inability, not a delay, of neural progenitors to generate motor neurons
- motor neuron differentiation does not occur at E9.5 in the hindbrain and spinal cord, however notochord, floorplate and neural tube differentiation appear normal

abnormal spinal cord interneuron morphology
- cultured cervical neural tube explants to not form interneurons, indicating a failure, and not a delay, of interneuron differentiation
- engrailed1 positive interneurons are absent in the neural tube of 25 somite stage embryos

decreased embryonic neuroepithelium thickness
- exhibit marked thinning of the neuroepithelium in the ventral neural tube

cellular phenotype

embryo tissue necrosis
- embryos are necrotic at E11.5

embryo phenotype

decreased embryo size
- embryos are smaller by E9-9.5

decreased embryonic neuroepithelium thickness
- exhibit marked thinning of the neuroepithelium in the ventral neural tube

embryo tissue necrosis
- embryos are necrotic at E11.5

embryonic growth arrest
- E10.5 embryos show no advance in development compared with E9.5, indicating arrested development soon after E9.5

growth/size/body region phenotype

decreased embryo size
- embryos are smaller by E9-9.5

mortality/aging

embryonic lethality during organogenesis, complete penetrance
- die by E11.5

Genotype: Isl1^tm1Tmj/Isl1^tm1Tmj
involves: 129S1/Sv

cardiovascular system phenotype

abnormal heart atrium morphology
- exhibit significant reduction in the amount of atrial tissue

abnormal heart development
- cardiac primorida at E8.75 resembles cardiac primordia seen in wild-type at E8.25, suggesting an interruption in heart development

abnormal heart shape
- hearts are misshapen at E9-9.5

absent cardiac outflow tract
- lack an outflow tract as indicated by marker analysis

absent heart right ventricle
- lack the right ventricle, although cells with left ventricular, A/V canal and atrial identities are present

failure of heart looping
- hearts are unlooped at E9-9.5

endocrine/exocrine gland phenotype

abnormal pancreas mesenchyme morphology
- dorsal pancreatic mesenchyme does not form

abnormal pancreas morphology

abnormal pancreatic acinar cell morphology
- exhibit failure of exocrine cell differentiation in the dorsal but not the ventral pancreas

abnormal pancreatic islet morphology
- cultured gut explants do not generate differentiated islet cells

abnormal Rathke's pouch development
- pouch cells are aberrant and fail to differentiate
- rudimentary pouch forms at E9.5, small and primitive

absent pancreatic alpha cells
- exhibit complete absence of islet (glucogon+) cells in E9.5 embryos

small Rathke's pouch
- at E9.5

mortality/aging

embryonic lethality during organogenesis, complete penetrance
- die around E10.5

nervous system phenotype

abnormal Rathke's pouch development
- pouch cells are aberrant and fail to differentiate
- rudimentary pouch forms at E9.5, small and primitive

small Rathke's pouch
- at E9.5

craniofacial phenotype

abnormal pharyngeal arch morphology
- exhibit decreased cell proliferation in pharyngeal endoderm

digestive/alimentary phenotype

abnormal pancreatic acinar cell morphology
- exhibit failure of exocrine cell differentiation in the dorsal but not the ventral pancreas

embryo phenotype

abnormal pharyngeal arch morphology
- exhibit decreased cell proliferation in pharyngeal endoderm

abnormal splanchnic mesoderm morphology
- exhibit decreased cell proliferation and increased apoptosis of splanchnic mesodermal cells that are immediately adjacent to pharyngeal endoderm at E8.75 or E9.5

embryonic growth arrest
- growth retardation at about E9.5

References

Pfaff SL; Mendelsohn M; Stewart CL; Edlund T; Jessell TM. 1996. Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation. Cell 84(2):309-20PubMed: 8565076 MGI: J:31131

Additional - Isl1^tm1Tmj related

Technical Support

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Genotyping Protocols
- SEPARATED MELT: Isl1^tm1Tmj Alternate2
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Breeding Considerations

When maintained as a live colony, heterozygotes may be bred. Homozygotes are embryonic lethal.
- Additional Breeding and Husbandry Support
Citation
When using the CB6-Isl1^tm1Tmj/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #009645 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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Cryorecovery - Pricing

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	Heterozygous or wildytpe for Isl1<tm1Tmj>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Selected References

Isl1tm1Tmj

Allele Symbol: Isl1tm1Tmj

Disease Terms

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Isl1tm1Tmj/Isl1tm1Tmjeither: 129S1/Sv-Isl1 or (involves: 129S1/Sv * C57BL/6J)

cardiovascular system phenotype

nervous system phenotype

cellular phenotype

embryo phenotype

growth/size/body region phenotype

mortality/aging

Genotype: Isl1tm1Tmj/Isl1tm1Tmjinvolves: 129S1/Sv

cardiovascular system phenotype

endocrine/exocrine gland phenotype

mortality/aging

nervous system phenotype

craniofacial phenotype

digestive/alimentary phenotype

embryo phenotype

References

Additional - Isl1tm1Tmj 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

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Isl1^tm1Tmj

Allele Symbol: Isl1^tm1Tmj

Genotype: Isl1^tm1Tmj/Isl1^tm1Tmj
either: 129S1/Sv-Isl1 or (involves: 129S1/Sv * C57BL/6J)

Genotype: Isl1^tm1Tmj/Isl1^tm1Tmj
involves: 129S1/Sv

Additional - Isl1^tm1Tmj related