Description

Strain Information

Type Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Generation N20F?+12 (08-JAN-08)   Donating Investigator Andrew McMahon,   Harvard University

Description
Mice that are homozygous for the Shh^tm2Amc targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. This conditional mutant contains two loxP sites flanking exon 2 of the targeted allele. Cre-mediated recombination excises exon 2 and some surrounding intronic sequence, generating a null allele. When the conditional mutant is crossed with a ubiquitously-expressing Cre recombinase carrier to remove Shh activity in the early embryo, the resulting phenotype resembles the Shh null mutation. These conditional mutant mice may be mated to strains expressing Cre recombinase to study the effects of temporal and tissue-specific ablation of the targeted allele. This mutant mouse strain represents a model that may be useful in studies of developmental defects resulting from disruption of Shh-dependent pathways.

When bred to a strain expressing Cre recombinase under the control of a tetracycline-responsive promoter element (see Stock No. 006224,006234, 006244) and a strain expressing a tetracycline-controlled activator protein in the lung and respiratory epithelium (see Stock No. 006225), this mutant mouse strain provides an inducible model for use in studies of hedgehog signalling in respiratory system development.

When bred to a strain with the targeted null allele (Stock No. 003318) and a strain expressing Cre recombinase in the skin and dental epithelium (Stock No. 004782), this mutant mouse strain may be useful in studies of hedgehog signalling and cell proliferation in the dental epithelium.

When bred to a strain expressing Cre recombinase in the nervous system (see Stock No. 003771 for example), this mutant mouse strain may be useful in studies of of hedgehog signalling in cortical interneurons.

Development
The original recombinant allele contained a neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter with flanking loxP sites. The PGK-Neo cassette was removed by Cre-mediated recombination in ES cells to produce the Shh conditional allele. In the Shh conditional allele, exon 2 is flanked by loxP sites. The construct was electroporated into 129 derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were backcrossed to 129X1 mice.

Control Information

	Control
	000691 129X1/SvJ
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Shh

000214	B10.D2/nSn-ShhHx/J
005623	B6.129S-Shhtm2(cre/ESR1)Cjt/J
008466	B6.129X1-Shhtm6Amc/J
005622	B6.Cg-Shhtm1(EGFP/cre)Cjt/J
003318	STOCK Shhtm1Amc/J

View Strains carrying other alleles of Shh     (5 strains)

Additional Web Information

Cre-lox Systems

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Shh^tm1Amc/Shh^tm2Amc Tg(KRT14-cre)1Amc/0

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA   (conditional)

• lethality-prenatal/perinatal
• neonatal lethality (MGI Ref ID J:65294)
  • mutant newborns die within a day after birth
• craniofacial phenotype
• abnormal ameloblast morphology (MGI Ref ID J:65294)
  • at birth, functional odontoblast and ameloblast layers are present but display abnormal polarity and cellular architecture
  • when early tooth rudiments (13.5-15.5 dpc) are transplanted under kidney capsules of nude mice, enamel and dentin matrices are deposited in spite of absent ameloblast elongation and odontoblast disorganization
• abnormal dentin morphology (MGI Ref ID J:65294)
  • in grafts of early tooth rudiments (13.5-15.5 dpc), dentin deposits are deposited but crown formation is incomplete and resulting teeth are small and abnormally shaped
• abnormal enamel morphology (MGI Ref ID J:65294)
  • at 14.5 dpc, the outer enamel epithelium of the lingual side is severely reduced and the lingual inner enamel epithelium has not invaginated, suggesting impaired crown formation
  • when early tooth rudiments (13.5-15.5 dpc) are transplanted under kidney capsules of nude mice, enamel matrix is secreted but crown formation is incomplete and resulting teeth are small and abnormally shaped
• abnormal incisor morphology (MGI Ref ID J:65294)
  • at birth, mutant pups display small (only 5% of normal size) and abnormally shaped incisors in both the mandible and maxilla
  • mandibular incisors display a single cusp with two symmetrical cervical loops; additional cusp formation is disrupted
• abnormal molar crown morphology (MGI Ref ID J:65294)
  • mandibular molars display a single irregular cusp; additional cusp formation is disrupted
• abnormal skull morphology (MGI Ref ID J:65294)
  • at birth, mutant pups display flattened skulls
• abnormal nasal bone morphology (MGI Ref ID J:65294)
  • at birth, mutant pups display a small frontal nasal process; nasal passageways are severely reduced
• absent alveolar process (MGI Ref ID J:65294)
  • mutant mandibular molars are fused with the oral ectoderm and the alveolar bone is absent
• arrest of tooth development (MGI Ref ID J:65294)
  • at birth, mutant pups show absence of obvious teeth: manidbular molars and incisors exhibit a cap stage tooth rudiment of abnormal morphology
• growth retardation of incisors (MGI Ref ID J:65294)
  • at birth, mandibular incisors are more developmentally advanced relative to mandibular molars
• growth retardation of molars (MGI Ref ID J:65294)
  • at birth, mandibular molars are less developmentally advanced relative to mandibular incisors
• cleft palate (MGI Ref ID J:90909)
  • 85% exhibit a cleft palate with rudimentary palatal shelves spaced widely apart
• small molars (MGI Ref ID J:65294)
  • at birth, mutant pups display small and abnormally shaped first molars in both the mandible and maxilla
  • maxillary molars are less affected than mandibular molars which are 25% of normal size
  • although cervical loops, dental papilla, inner enamel epithelium, predentin, and stellate reticulum are present, no dental cord is formed
• skeleton phenotype
• *normal* skeleton phenotype (MGI Ref ID J:65294)
  • at birth, mutant pups possess normal skeletal elements; the upper and lower jaws are of normal length
• abnormal ameloblast morphology (MGI Ref ID J:65294)
  • at birth, functional odontoblast and ameloblast layers are present but display abnormal polarity and cellular architecture
  • when early tooth rudiments (13.5-15.5 dpc) are transplanted under kidney capsules of nude mice, enamel and dentin matrices are deposited in spite of absent ameloblast elongation and odontoblast disorganization
• abnormal skull morphology (MGI Ref ID J:65294)
  • at birth, mutant pups display flattened skulls
• abnormal nasal bone morphology (MGI Ref ID J:65294)
  • at birth, mutant pups display a small frontal nasal process; nasal passageways are severely reduced
• absent alveolar process (MGI Ref ID J:65294)
  • mutant mandibular molars are fused with the oral ectoderm and the alveolar bone is absent
• arrest of tooth development (MGI Ref ID J:65294)
  • at birth, mutant pups show absence of obvious teeth: manidbular molars and incisors exhibit a cap stage tooth rudiment of abnormal morphology
• growth retardation of incisors (MGI Ref ID J:65294)
  • at birth, mandibular incisors are more developmentally advanced relative to mandibular molars
• growth retardation of molars (MGI Ref ID J:65294)
  • at birth, mandibular molars are less developmentally advanced relative to mandibular incisors
• vision/eye phenotype
• eyelids open at birth (MGI Ref ID J:65294)
• touch/vibrissae phenotype
• absent vibrissae (MGI Ref ID J:65294)
• respiratory system phenotype
• abnormal breathing (MGI Ref ID J:65294)
  • at birth, mutant pups are observed gulping air
• digestive/alimentary phenotype
• cleft palate (MGI Ref ID J:90909)
  • 85% exhibit a cleft palate with rudimentary palatal shelves spaced widely apart

Shh^tm2Amc/Shh^tm2Amc Tg(Nes-cre)1Kln/0

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL   (conditional)

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:102950)
  • death by P15
• growth/size phenotype
• postnatal growth retardation (MGI Ref ID J:102950)
  • marked reduction in growth by the second postnatal week
• craniofacial phenotype
• microcephaly (MGI Ref ID J:102950)
• nervous system phenotype
• abnormal medial ganglionic eminence morphology (MGI Ref ID J:102950)
  • reduced interneuron fate determining gene Nkx2.1 expression in progenitors of the medial ganglionic eminence (MGE) cells in S-phase
  • a subtle disruption of MGE patterning indicated by reduction of Gli1 and Nkx6.2 expression is observed
  • however, other aspects of MGE progenitor identity are maintained
• decreased brain size (MGI Ref ID J:102950)
  • 10% decrease in cortical thickness at P12
• decreased interneuron number (MGI Ref ID J:102950)
  • reductions of somatostatin- and parvalbumin-expressing interneurons in somatosensory cortex
  • somatostatin- and Npy-expressing interneurons are also reduced in the striatum
• seizures (MGI Ref ID J:102950)
  • pronounced extension of the hindlimbs in response to handling and seizure-like behavior by the second postnatal week
• behavior/neurological phenotype
• seizures (MGI Ref ID J:102950)
  • pronounced extension of the hindlimbs in response to handling and seizure-like behavior by the second postnatal week

Shh^tm2Amc/Shh^tm2Amc Tg(SFTPC-rtTA)5Jaw/0 Tg(tetO-cre)1Jaw/0

        involves: FVB/N   (conditional)

• lethality-prenatal/perinatal
• neonatal lethality (MGI Ref ID J:91723)
  • mutants die shortly after birth when doxycycline is administered throughout gestation
  • in the absence of doxycycline mutants are viable
• respiratory system phenotype
• abnormal lung morphology (MGI Ref ID J:91723)
  • lung and airway malformations are seen when doxycycline exposure occurs between E0.5 and E13.5
  • doxycycline exposure after E13.5 does not result in any pulmonary or extrapulmonary abnormalities
• abnormal bronchus morphology (MGI Ref ID J:91723)
  • peripheral tubule dilation is seen after doxycycline exposure
• lung cysts (MGI Ref ID J:91723)
  • cysts that contain neuroepithelial cells are seen in the peripheral lung tissue
• pulmonary hypoplasia (MGI Ref ID J:91723)
  • lungs are hypoplastic when doxycycline is administered throughout gestation
• abnormal trachea morphology (MGI Ref ID J:91723)
  • tracheal abnormalities are seen
  • doxycycline exposure before E8.5 or after E13.5 does not result in tracheal abnormalities
• abnormal tracheal cartilage morphology (MGI Ref ID J:91723)
  • the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure
  • fewer cartilaginous rings are seen after doxycycline exposure
• abnormal tracheal-bronchial branching morphogenesis (MGI Ref ID J:91723)
  • branching morphogenesis is abnormal
• skeleton phenotype
• abnormal tracheal cartilage morphology (MGI Ref ID J:91723)
  • the cartilaginous rings that normal surround the trachea are malformed with incomplete rings found along the ventral midline after doxycycline exposure
  • fewer cartilaginous rings are seen after doxycycline exposure

View Research Applications

Research Applications

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

Neurobiology Research
Cre-lox System (loxP-flanked Sequences)

Research Tools
Cre-lox System (loxP-flanked Sequences)

Shh^tm2Amc related

Cancer Research
Genes Regulating Growth and Proliferation
Growth Factors/Receptors/Cytokines
Oncogenes

Cell Biology Research
Genes Regulating Growth and Proliferation

Dermatology Research
Skin and Hair Texture Defects

Developmental Biology Research
Craniofacial and Palate Defects
Embryonic Lethality (Homozygous)
Eye Defects
Growth Defects
Internal/Organ Defects
Neural Tube Defects
Neurodevelopmental Defects
Postnatal Mortality
Skeletal Defects

Neurobiology Research
Neural Tube Defects
Neurodevelopmental Defects

Sensorineural Research
Eye Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Shhtm2Amc
Allele Name		targeted mutation 2, Andrew P McMahon
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		ShhC-NShh; Shhc; Shhf; Shhflx;
Mutation Made By		Paula Lewis,   AstraZeneca, R&D Boston
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Shh, sonic hedgehog
Chromosome		5
Gene Common Name(s)		Dsh; HHG1; HLP3; HPE3; Hhg1; Hx; Hxl3; M100081; MCOPCB5; SMMCI; TPT; TPTPS; hedgehog gene 1; hemimelic extra toes; hemimelic extratoes like 3; short digits;
Molecular Note		LoxP sites were inserted into intronic sequences flanking exon 2. This mutation has no effect on the normal function of this gene. [MGI Ref ID J:65294]

Genotyping

Genotyping Information

Genotyping Protocols

Shh^tm2Amc, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Lewis PM; Dunn MP; McMahon JA; Logan M; Martin JF; St-Jacques B; McMahon AP. 2001. Cholesterol modification of sonic hedgehog is required for long-range signaling activity and effective modulation of signaling by Ptc1. Cell 105(5):599-612. [PubMed: 11389830]  [MGI Ref ID J:69771]

Additional References

Aoto K; Nishimura T; Eto K; Motoyama J. 2002. Mouse GLI3 Regulates Fgf8 Expression and Apoptosis in the Developing Neural Tube, Face, and Limb Bud. Dev Biol 251(2):320-32. [PubMed: 12435361]  [MGI Ref ID J:80177]

Machold R; Hayashi S; Rutlin M; Muzumdar MD; Nery S; Corbin JG; Gritli-Linde A; Dellovade T; Porter JA; Rubin LL; Dudek H; McMahon AP; Fishell G. 2003. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39(6):937-50. [PubMed: 12971894]  [MGI Ref ID J:85603]

Wang YP; Dakubo G; Howley P; Campsall KD; Mazarolle CJ; Shiga SA; Lewis PM; McMahon AP; Wallace VA. 2002. Development of normal retinal organization depends on Sonic hedgehog signaling from ganglion cells. Nat Neurosci 5(9):831-2. [PubMed: 12195432]  [MGI Ref ID J:78708]

Shh^tm2Amc related

Balmer CW; LaMantia AS. 2004. Loss of Gli3 and Shh function disrupts olfactory axon trajectories. J Comp Neurol 472(3):292-307. [PubMed: 15065125]  [MGI Ref ID J:109287]

Dakubo GD; Beug ST; Mazerolle CJ; Thurig S; Wang Y; Wallace VA. 2008. Control of glial precursor cell development in the mouse optic nerve by sonic hedgehog from retinal ganglion cells. Brain Res 1228:27-42. [PubMed: 18625210]  [MGI Ref ID J:139978]

Dakubo GD; Wang YP; Mazerolle C; Campsall K; McMahon AP; Wallace VA. 2003. Retinal ganglion cell-derived sonic hedgehog signaling is required for optic disc and stalk neuroepithelial cell development. Development 130(13):2967-80. [PubMed: 12756179]  [MGI Ref ID J:83530]

Dassule HR; Lewis P; Bei M; Maas R; McMahon AP. 2000. Sonic hedgehog regulates growth and morphogenesis of the tooth Development 127(22):4775-85. [PubMed: 11044393]  [MGI Ref ID J:65294]

El-Jaick KB; Powers SE; Bartholin L; Myers KR; Hahn J; Orioli IM; Ouspenskaia M; Lacbawan F; Roessler E; Wotton D; Muenke M. 2007. Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol Genet Metab 90(1):97-111. [PubMed: 16962354]  [MGI Ref ID J:116565]

Ferri AL; Lin W; Mavromatakis YE; Wang JC; Sasaki H; Whitsett JA; Ang SL. 2007. Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development 134(15):2761-9. [PubMed: 17596284]  [MGI Ref ID J:124122]

Gritli-Linde A; Hallberg K; Harfe BD; Reyahi A; Kannius-Janson M; Nilsson J; Cobourne MT; Sharpe PT; McMahon AP; Linde A. 2007. Abnormal hair development and apparent follicular transformation to mammary gland in the absence of hedgehog signaling. Dev Cell 12(1):99-112. [PubMed: 17199044]  [MGI Ref ID J:117334]

Hayashi S; Lewis P; Pevny L; McMahon AP. 2002. Efficient gene modulation in mouse epiblast using a Sox2Cre transgenic mouse strain. Mech Dev 119 Suppl 1:S97-S101. [PubMed: 14516668]  [MGI Ref ID J:83040]

Jacob J; Ferri AL; Milton C; Prin F; Pla P; Lin W; Gavalas A; Ang SL; Briscoe J. 2007. Transcriptional repression coordinates the temporal switch from motor to serotonergic neurogenesis. Nat Neurosci 10(11):1433-9. [PubMed: 17922007]  [MGI Ref ID J:128441]

Komada M; Saitsu H; Kinboshi M; Miura T; Shiota K; Ishibashi M. 2008. Hedgehog signaling is involved in development of the neocortex. Development 135(16):2717-27. [PubMed: 18614579]  [MGI Ref ID J:138572]

Lewis PM; Gritli-Linde A; Smeyne R; Kottmann A; McMahon AP. 2004. Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum. Dev Biol 270(2):393-410. [PubMed: 15183722]  [MGI Ref ID J:92189]

Machold R; Hayashi S; Rutlin M; Muzumdar MD; Nery S; Corbin JG; Gritli-Linde A; Dellovade T; Porter JA; Rubin LL; Dudek H; McMahon AP; Fishell G. 2003. Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron 39(6):937-50. [PubMed: 12971894]  [MGI Ref ID J:85603]

Miller LA; Wert SE; Clark JC; Xu Y; Perl AK; Whitsett JA. 2004. Role of Sonic hedgehog in patterning of tracheal-bronchial cartilage and the peripheral lung. Dev Dyn 231(1):57-71. [PubMed: 15305287]  [MGI Ref ID J:91723]

Rice R; Spencer-Dene B; Connor EC; Gritli-Linde A; McMahon AP; Dickson C; Thesleff I; Rice DP. 2004. Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate. J Clin Invest 113(12):1692-700. [PubMed: 15199404]  [MGI Ref ID J:90909]

Tian H; Jeong J; Harfe BD; Tabin CJ; McMahon AP. 2005. Mouse Disp1 is required in sonic hedgehog-expressing cells for paracrine activity of the cholesterol-modified ligand. Development 132(1):133-42. [PubMed: 15576405]  [MGI Ref ID J:94270]

Tsiairis CD; McMahon AP. 2008. Disp1 regulates growth of mammalian long bones through the control of Ihh distribution. Dev Biol 317(2):480-5. [PubMed: 18395198]  [MGI Ref ID J:136115]

Wang Y; Dakubo GD; Thurig S; Mazerolle CJ; Wallace VA. 2005. Retinal ganglion cell-derived sonic hedgehog locally controls proliferation and the timing of RGC development in the embryonic mouse retina. Development 132(22):5103-13. [PubMed: 16236765]  [MGI Ref ID J:103124]

Wang YP; Dakubo G; Howley P; Campsall KD; Mazarolle CJ; Shiga SA; Lewis PM; McMahon AP; Wallace VA. 2002. Development of normal retinal organization depends on Sonic hedgehog signaling from ganglion cells. Nat Neurosci 5(9):831-2. [PubMed: 12195432]  [MGI Ref ID J:78708]

Xu Q; Wonders CP; Anderson SA. 2005. Sonic hedgehog maintains the identity of cortical interneuron progenitors in the ventral telencephalon. Development 132(22):4987-98. [PubMed: 16221724]  [MGI Ref ID J:102950]

Yu J; Carroll TJ; McMahon AP. 2002. Sonic hedgehog regulates proliferation and differentiation of mesenchymal cells in the mouse metanephric kidney. Development 129(22):5301-12. [PubMed: 12399320]  [MGI Ref ID J:79481]

Zhu J; Nakamura E; Nguyen MT; Bao X; Akiyama H; Mackem S. 2008. Uncoupling Sonic hedgehog control of pattern and expansion of the developing limb bud. Dev Cell 14(4):624-32. [PubMed: 18410737]  [MGI Ref ID J:135157]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	This strain originated on a 129 background, has been intercrossed for 20 generations on the same and is now maintained as a homozygous line. Coat color expected from breeding:Agouti
Mating System	Homozygote x Homozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	000691 129X1/SvJ
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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.

---

Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

For additional Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.