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

Appearance
black
Related Genotype: a/a

Description
Mutant mice have a targeted mutation of the apolipoprotein E receptor Lrp8 (also called Apoer2). Homozygotes are viable with no gross morphological abnormalities. Homozygous males have reduced fertility, while females are not affected. Using C-terminal specific antibodies, no endogenous protein is detected in the brains of homozygotes. Homozygous mice have a smaller and less foliated cerebellum with various hippocampus defects in granule cell positioning, cortical neuron migration, granule cell laminar organization, commissural fiber distribution, CA1 microtubule-associated protein 2 (MAP-2) distribution, and long term potentiation (LTP). Mutant mice show contextual fear conditioning deficits. These mice may be useful in studies of brain development, neuronal cytoarchitecture, Reelin signaling pathways, NMDA receptor activity, lipoprotein receptors, synaptic plasticity and learning, schizophrenia, and neurodegenerative disorders such as Alzheimer's disease.

Development
A targeting vector was designed to replace exons 17 and 18 of the endogenous gene with a pol2neo cassette. These two exons encode most of the membrane-spanning segment and a portion of the cytoplasmic tail. The construct was electroporated into 129S6/SvEvTac-derived SM1 embryonic stem (ES) cells. Mutant mice were maintained on a mixed C57BL/6 and 129S6 background before arriving at The Jackson Laboratory.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

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. Myocardial Infarction, Susceptibility to   (LRP8)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

Lrp8^tm1Her/Lrp8^tm1Her

        involves: 129S6/SvEvTac * C57BL/6J

• nervous system phenotype
• abnormal lateral ventricle morphology
  • neuroblasts invade the lateral ventricle   (MGI Ref ID J:121846)
• abnormal postnatal subventricular zone morphology
  • some neuroblasts accumulate in the subventricular zone   (MGI Ref ID J:121846)
• abnormal rostral migratory stream morphology
  • rostral migratory streaming is only slightly disrupted with the accumulation of some neuroblasts in the subventricular zone   (MGI Ref ID J:121846)

Lrp8^tm1Her/Lrp8^tm1Her

        involves: 129S6/SvEvTac * C57BL/6

• nervous system phenotype
• abnormal cerebral cortex morphology
  • cortical layer abnormalities, with some laminar dispersion of upper layer neurons   (MGI Ref ID J:129338)
• abnormal hippocampus pyramidal cell layer
  • mutants exhibit a modest split of the pyramidal layer in area CA1 and CA3   (MGI Ref ID J:129338)

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

Lrp8^tm1Her/Lrp8^tm1Her

        involves: 129S6/SvEvTac

• reproductive system phenotype
• abnormal sperm physiology
  • mutant spermatozoa from the cauda epididymidis fail to regulate the intracellular osmotic pressure ("cell volume decrease")   (MGI Ref ID J:84102)
  • as a result, sperm fail to counteract water influx when released into hypo-osmotic conditions, causing cell swelling and coiling of the sperm tail   (MGI Ref ID J:84102)
• • asthenozoospermia
    • the % of motile mutant sperm is reduced to half the wild-type control value   (MGI Ref ID J:84102)
    • although curvilinear velocity and the amplitude of lateral head displacement remain normal, all other sperm analysis parameters are significantly reduced indicating ineffective forward progression   (MGI Ref ID J:84102)
• abnormal spermatogenesis
  • male homozygotes display abnormal sperm maturation in the proximal epididymis   (MGI Ref ID J:84102)
  • however, mutant testicular and epididymal structures exhibit normal development, and spermatozoa descending from the seminiferous tubules of the testis into the initial segment of the epididymis are morphologically normal   (MGI Ref ID J:84102)
• • abnormal sperm flagellum morphology
    • after exit from the initial epididymal segment, distinct tail abnormalities are increasingly observed during transit of sperm through the epididymal duct   (MGI Ref ID J:84102)
  • • abnormal sperm midpiece morphology
      • some sperm mid-pieces show abnormal kinking and fraying of axonemal structures   (MGI Ref ID J:84102)
    • • abnormal sperm mitochondrial sheath morphology
        • unlike wild-type, most mutant spermatozoa exhibit a highly irregular mitochondrial helix in mid-piece sections of the sperm tail   (MGI Ref ID J:84102)
    • coiled sperm flagellum
      • ~51% of mutant spermatozoa from the cauda epididymidis display coiling of the tail with a variable degree of bending   (MGI Ref ID J:84102)
      • ~49% show normal straight tail morphology   (MGI Ref ID J:84102)
    • hairpin sperm flagellum
      • 43% of mutant spermatozoa from the cauda epididymidis exhibit hairpin structures (180 degrees)   (MGI Ref ID J:84102)
      • hairpin morphology is completely reverted upon incubation in buffer containing mild detergents (0.1% Triton X-100), indicating cell volume dysregulation   (MGI Ref ID J:84102)
    • kinked sperm flagellum
      • 8% of mutant spermatozoa from the cauda epididymidis show slight angulations (<90 degrees)   (MGI Ref ID J:84102)
• male infertility   (MGI Ref ID J:55691)
  • male infertility is associated with reduced expression of a sperm maturation protein (GPX4) in the epididymis   (MGI Ref ID J:84102)
• behavior/neurological phenotype
• abnormal contextual conditioning behavior
  • contextual fear-conditioned learning deficits   (MGI Ref ID J:55691)
• abnormal spatial learning
  • homozygotes spent less time in the training quadrant and crossed the former platform position less often in probe trials compared to wild-type mice   (MGI Ref ID J:100988)
• nervous system phenotype
• abnormal Purkinje cell morphology
  • abnormal aggregates of Purkinje cells and cortical neurons   (MGI Ref ID J:55691)
• abnormal brain development
  • cortical layering disrupted, with neurons packed into tight horizontal layers   (MGI Ref ID J:55691)
• • abnormal cerebellar foliation
    • less foliated than wild-type   (MGI Ref ID J:55691)
• abnormal cerebral cortex morphology
  • at P21, markers for cortical layer 6 and subplate neurons have broadened expression, indicating that neurons are infiltrating layers closer to the cortical surface   (MGI Ref ID J:105699)
• abnormal dentate gyrus morphology
  • neurons in the dentate gyrus were very loosely packed   (MGI Ref ID J:55691)
  • ectopic calbindin-positive cells are located mainly in the polymorph layer between the densely packed granule layers   (MGI Ref ID J:105699)
• abnormal hippocampus layer morphology
  • ectopic calbindin-positive cells are located mainly in the polymorph layer between the densely packed granule layers   (MGI Ref ID J:105699)
• abnormal neuronal migration
  • corticospinal neurons are mislocalized to layers 4 and 6 of cerebral cortex   (MGI Ref ID J:117956)
• small cerebellum   (MGI Ref ID J:55691)
• cellular phenotype
• abnormal cell death
  • in mutants, corticospinal neurons are resistant to lesion-induced cell death whereas ~40% of wild-type CSN die after CSN deafferentation at 1 month of age; at 4 months, survival ratio is similar   (MGI Ref ID J:117956)
• abnormal neuronal migration
  • corticospinal neurons are mislocalized to layers 4 and 6 of cerebral cortex   (MGI Ref ID J:117956)

View Research Applications

Research Applications

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

Lrp8^tm1Her related

Developmental Biology Research
Defects in Extracellular Matrix Molecules
Neurodevelopmental Defects

Neurobiology Research
Cerebellar Defects
Cortical Defects
Neurodevelopmental Defects
Receptor Defects
Tremor Defects

Research Tools
Neurobiology Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Lrp8tm1Her
Allele Name		targeted mutation 1, Joachim Herz
Allele Type		Targeted (knock-out)
Common Name(s)		ApoER2-;
Mutation Made By		Dr. Joachim Herz,   Univ of Texas Southwest Med Ctr Dallas
Strain of Origin		129S6/SvEvTac
ES Cell Line Name		SM1
ES Cell Line Strain		129S6/SvEvTac
Gene Symbol and Name		Lrp8, low density lipoprotein receptor-related protein 8, apolipoprotein e receptor
Chromosome		4
Gene Common Name(s)		4932703M08Rik; AA921429; AI848122; APOER2; HSZ75190; LRP-8; Lr8b; MCI1; RIKEN cDNA 4932703M08 gene; cDNA sequence AA921429; expressed sequence AI848122; low density lipoprotein receptor relative, 8 ligand binding repeats, brain;
Molecular Note		A neomycin resistance cassette replaced exons 17 and 18, which encode most of the membrane spanning segment and part of the cytoplasmic tail. [MGI Ref ID J:55691]

Genotyping

Genotyping Information

Genotyping Protocols

Lrp8^tm1Her, Melt Curve Analysis
Lrp8^tm1Her, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Trommsdorff M; Gotthardt M; Hiesberger T; Shelton J; Stockinger W ; Nimpf J ; Hammer RE ; Richardson JA ; Herz J. 1999. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97(6):689-701. [PubMed: 10380922]  [MGI Ref ID J:55691]

Additional References

Drakew A; Deller T; Heimrich B; Gebhardt C; Del Turco D; Tielsch A; Forster E; Herz J; Frotscher M. 2002. Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice. Exp Neurol 176(1):12-24. [PubMed: 12093079]  [MGI Ref ID J:78001]

Gebhardt C; Del Turco D; Drakew A; Tielsch A; Herz J; Frotscher M; Deller T. 2002. Abnormal positioning of granule cells alters afferent fiber distribution in the mouse fascia dentata: Morphologic evidence from reeler, apolipoprotein E receptor 2-, and very low density lipoprotein receptor knockout mice. J Comp Neurol 445(3):278-92. [PubMed: 11920707]  [MGI Ref ID J:75080]

Weiss KH; Johanssen C; Tielsch A; Herz J; Deller T; Frotscher M; Forster E. 2003. Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice. J Comp Neurol 460(1):56-65. [PubMed: 12687696]  [MGI Ref ID J:83151]

Lrp8^tm1Her related

Akopians AL; Babayan AH; Beffert U; Herz J; Basbaum AI; Phelps PE. 2008. Contribution of the Reelin signaling pathways to nociceptive processing. Eur J Neurosci 27(3):523-37. [PubMed: 18279306]  [MGI Ref ID J:132269]

Andersen OM; Yeung CH; Vorum H; Wellner M; Andreassen TK; Erdmann B; Mueller EC; Herz J; Otto A; Cooper TG; Willnow TE. 2003. Essential role of the apolipoprotein E receptor-2 in sperm development. J Biol Chem 278(26):23989-95. [PubMed: 12695510]  [MGI Ref ID J:84102]

Andrade N; Komnenovic V; Blake SM; Jossin Y; Howell B; Goffinet A; Schneider WJ; Nimpf J. 2007. ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin. Proc Natl Acad Sci U S A 104(20):8508-13. [PubMed: 17494763]  [MGI Ref ID J:121846]

Assadi AH; Zhang G; Beffert U; McNeil RS; Renfro AL; Niu S; Quattrocchi CC; Antalffy BA; Sheldon M; Armstrong DD; Wynshaw-Boris A; Herz J; D'Arcangelo G; Clark GD. 2003. Interaction of reelin signaling and Lis1 in brain development. Nat Genet 35(3):270-6. [PubMed: 14578885]  [MGI Ref ID J:86398]

Barr AM; Fish KN; Markou A. 2007. The reelin receptors VLDLR and ApoER2 regulate sensorimotor gating in mice. Neuropharmacology 52(4):1114-23. [PubMed: 17261317]  [MGI Ref ID J:124495]

Beffert U; Durudas A; Weeber EJ; Stolt PC; Giehl KM; Sweatt JD; Hammer RE; Herz J. 2006. Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J Neurosci 26(7):2041-52. [PubMed: 16481437]  [MGI Ref ID J:105699]

Beffert U; Nematollah Farsian F; Masiulis I; Hammer RE; Yoon SO; Giehl KM; Herz J. 2006. ApoE receptor 2 controls neuronal survival in the adult brain. Curr Biol 16(24):2446-52. [PubMed: 17174920]  [MGI Ref ID J:117956]

Beffert U; Weeber EJ; Morfini G; Ko J; Brady ST; Tsai LH; Sweatt JD; Herz J. 2004. Reelin and cyclin-dependent kinase 5-dependent signals cooperate in regulating neuronal migration and synaptic transmission. J Neurosci 24(8):1897-906. [PubMed: 14985430]  [MGI Ref ID J:90122]

Blake SM; Strasser V; Andrade N; Duit S; Hofbauer R; Schneider WJ; Nimpf J. 2008. Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration. EMBO J 27(22):3069-80. [PubMed: 18946489]  [MGI Ref ID J:143787]

Burk RF; Hill KE; Olson GE; Weeber EJ; Motley AK; Winfrey VP; Austin LM. 2007. Deletion of apolipoprotein E receptor-2 in mice lowers brain selenium and causes severe neurological dysfunction and death when a low-selenium diet is fed. J Neurosci 27(23):6207-11. [PubMed: 17553992]  [MGI Ref ID J:121972]

Cariboni A; Rakic S; Liapi A; Maggi R; Goffinet A; Parnavelas JG. 2005. Reelin provides an inhibitory signal in the migration of gonadotropin-releasing hormone neurons. Development 132(21):4709-18. [PubMed: 16207762]  [MGI Ref ID J:102848]

Drakew A; Deller T; Heimrich B; Gebhardt C; Del Turco D; Tielsch A; Forster E; Herz J; Frotscher M. 2002. Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice. Exp Neurol 176(1):12-24. [PubMed: 12093079]  [MGI Ref ID J:78001]

Dumanis SB; Cha HJ; Song JM; Trotter JH; Spitzer M; Lee JY; Weeber EJ; Turner RS; Pak DT; Rebeck GW; Hoe HS. 2011. ApoE receptor 2 regulates synapse and dendritic spine formation. PLoS One 6(2):e17203. [PubMed: 21347244]  [MGI Ref ID J:171098]

Fish KN; Krucker T. 2008. Functional consequences of hippocampal neuronal ectopia in the apolipoprotein E receptor-2 knockout mouse. Neurobiol Dis 32(3):391-401. [PubMed: 18778775]  [MGI Ref ID J:142541]

Gebhardt C; Del Turco D; Drakew A; Tielsch A; Herz J; Frotscher M; Deller T. 2002. Abnormal positioning of granule cells alters afferent fiber distribution in the mouse fascia dentata: Morphologic evidence from reeler, apolipoprotein E receptor 2-, and very low density lipoprotein receptor knockout mice. J Comp Neurol 445(3):278-92. [PubMed: 11920707]  [MGI Ref ID J:75080]

Hack I; Hellwig S; Junghans D; Brunne B; Bock HH; Zhao S; Frotscher M. 2007. Divergent roles of ApoER2 and Vldlr in the migration of cortical neurons. Development 134(21):3883-91. [PubMed: 17913789]  [MGI Ref ID J:126335]

Hashimoto-Torii K; Torii M; Sarkisian MR; Bartley CM; Shen J; Radtke F; Gridley T; Sestan N; Rakic P. 2008. Interaction between Reelin and Notch signaling regulates neuronal migration in the cerebral cortex. Neuron 60(2):273-84. [PubMed: 18957219]  [MGI Ref ID J:144065]

Jossin Y; Gui L; Goffinet AM. 2007. Processing of Reelin by embryonic neurons is important for function in tissue but not in dissociated cultured neurons. J Neurosci 27(16):4243-52. [PubMed: 17442808]  [MGI Ref ID J:121108]

Kruger MT; Zhao S; Chai X; Brunne B; Bouche E; Bock HH; Frotscher M. 2010. Role for Reelin-induced cofilin phosphorylation in the assembly of sympathetic preganglionic neurons in the murine intermediolateral column. Eur J Neurosci 32(10):1611-7. [PubMed: 21039973]  [MGI Ref ID J:169495]

Larouche M; Beffert U; Herz J; Hawkes R. 2008. The reelin receptors apoer2 and vldlr coordinate the patterning of purkinje cell topography in the developing mouse cerebellum. PLoS ONE 3(2):e1653. [PubMed: 18301736]  [MGI Ref ID J:132885]

Leemhuis J; Bouche E; Frotscher M; Henle F; Hein L; Herz J; Meyer DK; Pichler M; Roth G; Schwan C; Bock HH. 2010. Reelin signals through apolipoprotein E receptor 2 and Cdc42 to increase growth cone motility and filopodia formation. J Neurosci 30(44):14759-72. [PubMed: 21048135]  [MGI Ref ID J:166701]

Masiulis I; Quill TA; Burk RF; Herz J. 2009. Differential functions of the Apoer2 intracellular domain in selenium uptake and cell signaling. Biol Chem 390(1):67-73. [PubMed: 19007311]  [MGI Ref ID J:153933]

Olson GE; Winfrey VP; Hill KE; Burk RF. 2008. Megalin mediates selenoprotein P uptake by kidney proximal tubule epithelial cells. J Biol Chem 283(11):6854-60. [PubMed: 18174160]  [MGI Ref ID J:133662]

Olson GE; Winfrey VP; Nagdas SK; Hill KE; Burk RF. 2007. Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein P by the mouse testis. J Biol Chem 282(16):12290-7. [PubMed: 17314095]  [MGI Ref ID J:121140]

Petit-Turcotte C; Aumont N; Beffert U; Dea D; Herz J; Poirier J. 2005. The apoE receptor apoER2 is involved in the maintenance of efficient synaptic plasticity. Neurobiol Aging 26(2):195-206. [PubMed: 15582748]  [MGI Ref ID J:101963]

Quinn KL; Henriques M; Tabuchi A; Han B; Yang H; Cheng WE; Tole S; Yu H; Luo A; Charbonney E; Tullis E; Lazarus A; Robinson LA; Ni H; Peterson BR; Kuebler WM; Slutsky AS; Zhang H. 2011. Human neutrophil peptides mediate endothelial-monocyte interaction, foam cell formation, and platelet activation. Arterioscler Thromb Vasc Biol 31(9):2070-9. [PubMed: 21817096]  [MGI Ref ID J:191841]

Ramesh S; Morrell CN; Tarango C; Thomas GD; Yuhanna IS; Girardi G; Herz J; Urbanus RT; de Groot PG; Thorpe PE; Salmon JE; Shaul PW; Mineo C. 2011. Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via beta2GPI and apoER2. J Clin Invest 121(1):120-31. [PubMed: 21123944]  [MGI Ref ID J:171855]

Romay-Penabad Z; Aguilar-Valenzuela R; Urbanus RT; Derksen RH; Pennings MT; Papalardo E; Shilagard T; Vargas G; Hwang Y; de Groot PG; Pierangeli SS. 2011. Apolipoprotein E receptor 2 is involved in the thrombotic complications in a murine model of the antiphospholipid syndrome. Blood 117(4):1408-14. [PubMed: 21119114]  [MGI Ref ID J:168586]

Rossel M; Loulier K; Feuillet C; Alonso S; Carroll P. 2005. Reelin signaling is necessary for a specific step in the migration of hindbrain efferent neurons. Development 132(6):1175-85. [PubMed: 15703280]  [MGI Ref ID J:97218]

Senturk A; Pfennig S; Weiss A; Burk K; Acker-Palmer A. 2011. Ephrin Bs are essential components of the Reelin pathway to regulate neuronal migration. Nature 472(7343):356-60. [PubMed: 21460838]  [MGI Ref ID J:171375]

Trotter JH; Klein M; Jinwal UK; Abisambra JF; Dickey CA; Tharkur J; Masiulis I; Ding J; Locke KG; Rickman CB; Birch DG; Weeber EJ; Herz J. 2011. ApoER2 Function in the Establishment and Maintenance of Retinal Synaptic Connectivity. J Neurosci 31(40):14413-14423. [PubMed: 21976526]  [MGI Ref ID J:177435]

Uchida T; Baba A; Perez-Martinez FJ; Hibi T; Miyata T; Luque JM; Nakajima K; Hattori M. 2009. Downregulation of functional Reelin receptors in projection neurons implies that primary Reelin action occurs at early/premigratory stages. J Neurosci 29(34):10653-62. [PubMed: 19710317]  [MGI Ref ID J:152314]

Weeber EJ; Beffert U; Jones C; Christian JM; Forster E; Sweatt JD; Herz J. 2002. Reelin and ApoE Receptors Cooperate to Enhance Hippocampal Synaptic Plasticity and Learning. J Biol Chem 277(42):39944-52. [PubMed: 12167620]  [MGI Ref ID J:79593]

Weiss KH; Johanssen C; Tielsch A; Herz J; Deller T; Frotscher M; Forster E. 2003. Malformation of the radial glial scaffold in the dentate gyrus of reeler mice, scrambler mice, and ApoER2/VLDLR-deficient mice. J Comp Neurol 460(1):56-65. [PubMed: 12687696]  [MGI Ref ID J:83151]

Zhang G; Assadi AH; McNeil RS; Beffert U; Wynshaw-Boris A; Herz J; Clark GD; D'Arcangelo G. 2007. The Pafah1b complex interacts with the Reelin receptor VLDLR. PLoS ONE 2(2):e252. [PubMed: 17330141]  [MGI Ref ID J:129338]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

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

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

General Supply Notes

• Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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.

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