Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse   Donating Investigator Dr. Joachim Herz,   Univ of Texas Southwest Med Ctr Dallas

Description
The Lrp4 hypomorphic allele (Lrp4ECD, Lrp4 EC STOP, Lrp4^hypo, Megf7^-, Lrp4STOP1723) contains a premature stop codon within the exon immediately upstream of the transmembrane segment. Much of the targeted exon and 3' adjacent intron is absent. No functional full-length transcripts are detected in brain tissue. The transcript generated is out of frame beyond the sequences coding for the transmembrane segment, which results in a truncated protein with loss of the transmembrane and intracellular domains of the LRP4 protein. While the LRP4 extracellular domain (ECD) is expressed normally, the lack of a membrane anchor leads to shedding/secretion of the ECD into the extracellular space. This results in diminished, but not completely absent, LRP4 interactions with its extracellular ligands (i.e., hypomorphic phenotype). Mice homozygous for this Lrp4 hypomorphic allele are viable and fertile. Homozygous mice exhibit growth retardation, fully penetrant polysyndactyly with digit fusions, abnormal tooth development and changes in Shh- and Wnt-signaling. The tooth development abnormalities include supernumerary incisors/molars of reduced size and abnormal shape, and incisors with grooved enamel surfaces that exhibit the same molecular characteristics as the tips of molar cusps. Homozygous mice also have defects in neuromuscular junction development, and bone growth and turnover. These mutant mice may be useful in studying the LRP4 extracellular domain in embryonic development (polysyndactyly, tooth, neuromuscular junction), as well as low-density lipoprotein (LDL) receptor family-, Shh-, Bmp-, and Wnt-signaling pathways.

Development
A targeting vector was designed by site-specific mutation to insert a stop codon into exon 36 (codon 1723) of the Lrp4 (or Megf7) locus, as well as replace part of exon 36 and 2.1 kb of intron 36 with a PGKneobpA expression cassette (loxP::frt::PGK-neo^r cassette::loxP::frt followed by bovine growth hormone polyA signal). This results in deletion of the downstream portion of exon 36 including the transmembrane and intracellular domains of the Lrp4 protein. This was designed at the time to prevent production of a membrane-anchored receptor and eliminate residual functional activity (through alternative splicing of the extracellular domain or via the potential use of alternative promoters for transcription initiation). The construct was electroporated into 129S6/SvEvTac-derived SM1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with C57BL/6 females to establish the colony. Mice on a mixed C57BL/6;129S6/SvEv genetic background were sent to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

Control Information

	Control
	Wild-type from the colony
	101043 B6129SF1/J	(approximate)
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Lrp4

004423	DBA/1LacJ-Lrp4mdig/GrsrJ
010968	SB;C3Sn-Lrp4mdig-2J/GrsrJ

View Strains carrying other alleles of Lrp4     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Cenani-Lenz Syndactyly Syndrome; CLSS   (LRP4) Sclerosteosis 2; SOST2   (LRP4)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Lrp4^tm1Her/Lrp4^tm1Her

        involves: 129S6/SvEvTac * C57BL/6

• mortality/aging
• partial preweaning lethality
  • number of homozygotes identified at P5 is much lower than expected, but up to approximately E13, numbers of each genotype is as expected   (MGI Ref ID J:106811)
• embryogenesis phenotype
• thick apical ectodermal ridge
  • the Fgf8-expressing AER is thickened and broadened in mutants   (MGI Ref ID J:106811)
• growth/size phenotype
• abnormal postnatal growth
  • homozygotes show significantly reduced body weights and postnatal growth compared with wild-type and heterozygotes   (MGI Ref ID J:106811)
• limbs/digits/tail phenotype
• abnormal digit morphology
  • examination 14 day-old mutants revealed fused digital bones and tendons, club-shaped deformities of digital tips and metaphyseal defects   (MGI Ref ID J:106811)
• • polydactyly
    • homozygous mice have fully penetrant polysyndactyly of both the fore- and hindlimbs;   (MGI Ref ID J:106811)
• abnormal forelimb morphology
  • extensive bone fusion can be seen in the forelimb   (MGI Ref ID J:106811)
• abnormal hindlimb morphology
  • extensive bone fusion can be seen in the hindlimb   (MGI Ref ID J:106811)
• thick apical ectodermal ridge
  • the Fgf8-expressing AER is thickened and broadened in mutants   (MGI Ref ID J:106811)
• craniofacial phenotype
• abnormal incisor morphology
  • mutants have mild craniofacial defects usually in the form of incisor defects   (MGI Ref ID J:106811)
• skeleton phenotype
• abnormal chondrocyte morphology
  • at E12.5, chondrocye compaction is apparent in the fore- and hindlimbs of mutants; the digital cartilage is broadly fused in mutants as seen at P0   (MGI Ref ID J:106811)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Lrp4^tm1Her/Lrp4^tm1Her

        involves: 129S6/SvEvTac

• craniofacial phenotype
• abnormal enamel morphology
  • grooves on incisors result from a localized reduction of enamel on the labial surface   (MGI Ref ID J:156471)
• abnormal incisor morphology
  • distinct grooved incisor labial surfaces   (MGI Ref ID J:156471)
• • supernumerary incisors
    • over one third show supernumerary maxillary incisor tooth germs at birth   (MGI Ref ID J:156471)

View Research Applications

Research Applications

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

Cell Biology Research
Signal Transduction

Developmental Biology Research
Growth Defects
      Growth Defects (homozygous)
Skeletal Defects
      polydactyly
      syndactyly

Neurobiology Research
Neuromuscular Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Lrp4tm1Her
Allele Name		targeted mutation 1, Joachim Herz
Allele Type		Targeted (knock-out)
Common Name(s)		Lrp4hypo; Lrp4ECD; Megf7-;
Mutation Made By		Dr. Joachim Herz,   Univ of Texas Southwest Med Ctr Dallas
Strain of Origin		129S6/SvEvTac
Gene Symbol and Name		Lrp4, low density lipoprotein receptor-related protein 4
Chromosome		2
Gene Common Name(s)		6430526J12Rik; CLSS; LRP-4; LRP10; MEGF7; RIKEN cDNA 6430526J12 gene; SOST2; malformed digits; mdig;
Molecular Note		The locus was disrupted by the insertion of a stop codon just upstream of the transmembrane segment. Part of exon 36 and 2.1 kb of intron 36 were replaced with a neomycin resistance cassette. RT-PCR confirmed the complete lack of functional transcripts. [MGI Ref ID J:106811]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(Akr1b7-RFP), Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Choi HY; Dieckmann M; Herz J; Niemeier A. 2009. Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo. PLoS One 4(11):e7930. [PubMed: 19936252]  [MGI Ref ID J:155399]

Dietrich MF; van der Weyden L; Prosser HM; Bradley A; Herz J; Adams DJ. 2010. Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo. PLoS One 5(4):e9960. [PubMed: 20383322]  [MGI Ref ID J:160170]

Johnson EB; Hammer RE; Herz J. 2005. Abnormal development of the apical ectodermal ridge and polysyndactyly in Megf7-deficient mice. Hum Mol Genet 14(22):3523-38. [PubMed: 16207730]  [MGI Ref ID J:106811]

Ohazama A; Blackburn J; Porntaveetus T; Ota MS; Choi HY; Johnson EB; Myers P; Oommen S; Eto K; Kessler JA; Kondo T; Fraser GJ; Streelman JT; Pardinas UF; Tucker AS; Ortiz PE; Charles C; Viriot L; Herz J; Sharpe PT. 2010. A role for suppressed incisor cuspal morphogenesis in the evolution of mammalian heterodont dentition. Proc Natl Acad Sci U S A 107(1):92-7. [PubMed: 20018657]  [MGI Ref ID J:156471]

Ohazama A; Johnson EB; Ota MS; Choi HJ; Porntaveetus T; Oommen S; Itoh N; Eto K; Gritli-Linde A; Herz J; Sharpe PT. 2008. Lrp4 modulates extracellular integration of cell signaling pathways in development. PLoS ONE 3(12):e4092. [PubMed: 19116665]  [MGI Ref ID J:144348]

Additional References

Lrp4^tm1Her related

Porntaveetus T; Ohazama A; Choi HY; Herz J; Sharpe PT. 2012. Wnt signaling in the murine diastema. Eur J Orthod 34(4):518-24. [PubMed: 21531785]  [MGI Ref ID J:186534]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry

When maintaining a live colony, heterozygous mice may be bred together or with wildtype mice from the colony. The donating investigator reports breeding homozygous mice with heterozygous mice, which allows the resulting pups to be identified visually (homozyotes may be identified by the obvious syndactyly, and the remainder of the offspring should be obligate heterozygotes). Of note, this should not be used to replace routine genotyping of the colony.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Wild-type from the colony
	101043 B6129SF1/J	(approximate)
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

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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.

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