Description

Strain Information

Former Names NOD.129P2(B6)-Cd38tm1Lnd/Lt    (Changed: 05-OCT-05 ) Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Edward Leiter,   The Jackson Laboratory

Description
NOD/Lt mice homozygous for the Cd38^tm1Lnd mutation are viable, fertile and exhibit accelerated Type 1 diabetes onset in females and males. This acceleration has been correlated with further impairment of an already subnormal immunoregulatory network. Regulatory T-cells from these mice are more sensitive to NAD-mediated apoptosis when compared to NOD/Lt controls. Similarly, NOD-characteristic reductions in NKT cell numbers are further exacerbated in homozygous NOD.Cd38^tm1Lnd mutant mice. Although CD38 is reportedly required for normal pancratic beta cell responses to glucose, this was not confirmed in congenic, doubly homozygous NOD.Pkrdc^scidCD38^tm1Lnd mutant mice.

NOD.129P2(B6)-Cd38^tm1Lnd/LtJ mice are valuable for understanding how systemic NAD metabolism can be used to alter immunoregulatory networks.

Development
CD38 (ADP ribosyl cyclase/cADPR hydrolase) is a Nicotinamide Adenine Dinucleotide (NAD) utilizing ectoenzyme involved in calcium mobilization. It is ubiquitously expressed to varying degrees on both hematopoietic and non-hematopoietic tissues. NAD released from target cell lysis that is not utilized by CD38 can elicit T cell apoptosis through the activity of another NAD-utilizing and T cell-specific ectoenzyme, ADP ribosyltransferase.A construct containing a neomycin expression cassette replacing exon 2 and 3 of Cd38 was transfected into E14-1 (129P2/OlaHsd-derived) embryonic stem cells (ES cells). These ES cells were injected into C57BL/6 blastocysts. As reported by Cockayne et al, 1998, chimeric founders were initially mated to C57BL/6 and intercrossed to generate homozygotes (B6.129P2-Cd38^tm1Lnd). B6.129P2-Cd38^tm1Lnd/J (stock# 3727)homozygote mice were subsequently mated to NOD/Lt for 11 generations prior to making homozygous. Marker assisted analysis indicates all known Idd loci are NOD/Lt in origin. In 2005, the T1DR received NOD.129P2(B6)-Cd38^tm1Lnd/LtJ at generation N11F5.

Control Information

	Control
	001976 NOD/ShiLtJ
Considerations for Choosing Controls

Related Strains

Strains carrying   Cd38^tm1Lnd allele

003727	B6.129P2-Cd38tm1Lnd/J
005347	NOD.129(B6)-Cd38tm1Lnd Art2atm1Fkn Art2btm1Fkn/Lt
005345	NOD.Cg-Cd38tm1Lnd Prkdcscid/LtJ

View Strains carrying   Cd38^tm1Lnd     (3 strains)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Diabetes Mellitus, Insulin-Dependent; IDDM - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Cd38^tm1Lnd/Cd38^tm1Lnd

        NOD.129P2(B6)-Cd38^tm1Lnd/LtJ

• immune system phenotype
• increased T cell apoptosis (MGI Ref ID J:108097)
  • Cd38-deficient NOD mice display higher NAD-mediated T cell death
• increased susceptibility to autoimmune diabetes (MGI Ref ID J:108097)
  • homozygous NOD mutants show significant acceleration in diabetes development compared to wild-type NOD mice; the first diagnosis of diabetes is made at 10 weeks of age while in wild-type NOD mice it occurs at 12 weeks or later; the frequency in null NOD males is 100% by 28 weeks which is higher than the frequency in wild-type NOD males
  • diabetes acceleration is seen only when Cd38-deficient bone marrow from NOD mice is transferred to Cd38-deficient recipients
  • diabetes onset is assessed by 2 consecutive positive urine glucose tests
• insulitis (MGI Ref ID J:108097)
  • insulitis progression in null NOD mice is accelerated at 9 weeks or later compared to wild-type NOD mice
• endocrine/exocrine gland phenotype
• insulitis (MGI Ref ID J:108097)
  • insulitis progression in null NOD mice is accelerated at 9 weeks or later compared to wild-type NOD mice
• digestive/alimentary phenotype
• insulitis (MGI Ref ID J:108097)
  • insulitis progression in null NOD mice is accelerated at 9 weeks or later compared to wild-type NOD mice
• hematopoietic system phenotype
• increased T cell apoptosis (MGI Ref ID J:108097)
  • Cd38-deficient NOD mice display higher NAD-mediated T cell death

View Research Applications

Research Applications

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

Cd38^tm1Lnd related

Cancer Research
Genes Regulating Growth and Proliferation

Diabetes and Obesity Research
Type 1 Diabetes (IDDM)

Immunology and Inflammation Research
CD Antigens, Antigen Receptors, and Histocompatibility Markers
Inflammation

Genes & Alleles

Gene & Allele Information

Allele Symbol		Cd38tm1Lnd
Allele Name		targeted mutation 1, Frances E Lund
Allele Type		Targeted (knock-out)
Common Name(s)		CD38-; CD38null;
Mutation Made By		Debra Cockayne,   Roche Bioscience
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14.1
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Cd38, CD38 antigen
Chromosome		5
Gene Common Name(s)		CD38 antigen, related sequence 1; Cd38-rs1; T10;
Molecular Note		A neomycin selection cassette replaced a genomic fragment containing exons 2 and 3, which encode the putative active site of the encoded protein. Homozygous mice lacked transcripts derived from this allele (data not shown). Flow cytometry analysis on splenocytes derived from homozygous mice confirmed that no detectable protein was expressed on the cell surface. [MGI Ref ID J:49170]

Genotyping

Genotyping Information

Genotyping Protocols

Cd38^tm1Ldn, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Chen J; Chen YG; Reifsnyder PC; Schott WH; Lee CH; Osborne M; Scheuplein F; Haag F; Koch-Nolte F; Serreze DV; Leiter EH. 2006. Targeted disruption of CD38 accelerates autoimmune diabetes in NOD/Lt mice by enhancing autoimmunity in an ADP-ribosyltransferase 2-dependent fashion. J Immunol 176(8):4590-9. [PubMed: 16585549]  [MGI Ref ID J:108097]

Chen YG; Chen J; Osborne MA; Chapman HD; Besra GS; Porcelli SA; Leiter EH; Wilson SB; Serreze DV. 2006. CD38 is required for the peripheral survival of immunotolerogenic CD4+ invariant NK T cells in nonobese diabetic mice. J Immunol 177(5):2939-47. [PubMed: 16920929]  [MGI Ref ID J:112615]

Additional References

Cd38^tm1Lnd related

Aksoy P; White TA; Thompson M; Chini EN. 2006. Regulation of intracellular levels of NAD: A novel role for CD38. Biochem Biophys Res Commun 345(4):1386-92. [PubMed: 16730329]  [MGI Ref ID J:109655]

Barbosa MT; Soares SM; Novak CM; Sinclair D; Levine JA; Aksoy P; Chini EN. 2007. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet-induced obesity. FASEB J 21(13):3629-39. [PubMed: 17585054]  [MGI Ref ID J:134922]

Bergthorsdottir S; Gallagher A; Jainandunsing S; Cockayne D; Sutton J; Leanderson T; Gray D. 2001. Signals that initiate somatic hypermutation of B cells in vitro. J Immunol 166(4):2228-34. [PubMed: 11160276]  [MGI Ref ID J:127146]

Ceni C; Pochon N; Villaz M; Muller-Steffner H; Schuber F; Baratier J; De Waard M; Ronjat M; Moutin MJ. 2006. The CD38-independent ADP-ribosyl cyclase from mouse brain synaptosomes: a comparative study of neonate and adult brain. Biochem J 395(2):417-26. [PubMed: 16411897]  [MGI Ref ID J:115899]

Cockayne DA; Muchamuel T; Grimaldi JC; Muller-Steffner H; Randall TD; Lund FE; Murray R; Schuber F; Howard MC. 1998. Mice deficient for the ecto-nicotinamide adenine dinucleotide Blood 92(4):1324-33. [PubMed: 9694721]  [MGI Ref ID J:49170]

Deshpande DA; White TA; Guedes AG; Milla C; Walseth TF; Lund FE; Kannan MS. 2005. Altered airway responsiveness in CD38-deficient mice. Am J Respir Cell Mol Biol 32(2):149-56. [PubMed: 15557017]  [MGI Ref ID J:107616]

Gul R; Kim SY; Park KH; Kim BJ; Kim SJ; Im MJ; Kim UH. 2008. A novel signaling pathway of ADP-ribosyl cyclase activation by angiotensin II in adult rat cardiomyocytes. Am J Physiol Heart Circ Physiol 295(1):H77-88. [PubMed: 18456728]  [MGI Ref ID J:138213]

Iqbal J; Zaidi M. 2006. TNF regulates cellular NAD+ metabolism in primary macrophages. Biochem Biophys Res Commun 342(4):1312-8. [PubMed: 16516847]  [MGI Ref ID J:107073]

Johnson JD; Ford EL; Bernal-Mizrachi E; Kusser KL; Luciani DS; Han Z; Tran H; Randall TD; Lund FE; Polonsky KS. 2006. Suppressed insulin signaling and increased apoptosis in CD38-null islets. Diabetes 55(10):2737-46. [PubMed: 17003338]  [MGI Ref ID J:116576]

Krebs C; Adriouch S; Braasch F; Koestner W; Leiter EH; Seman M; Lund FE; Oppenheimer N; Haag F; Koch-Nolte F. 2005. CD38 controls ADP-ribosyltransferase-2-catalyzed ADP-ribosylation of T cell surface proteins. J Immunol 174(6):3298-305. [PubMed: 15749861]  [MGI Ref ID J:97699]

Manjarrez-Orduno N; Moreno-Garcia ME; Fink K; Santos-Argumedo L. 2007. CD38 cross-linking enhances TLR-induced B cell proliferation but decreases IgM plasma cell differentiation. Eur J Immunol 37(2):358-67. [PubMed: 17274001]  [MGI Ref ID J:117900]

Mayo L; Jacob-Hirsch J; Amariglio N; Rechavi G; Moutin MJ; Lund FE; Stein R. 2008. Dual role of CD38 in microglial activation and activation-induced cell death. J Immunol 181(1):92-103. [PubMed: 18566373]  [MGI Ref ID J:137179]

Partida-Sanchez S; Cockayne DA; Monard S; Jacobson EL; Oppenheimer N; Garvy B; Kusser K; Goodrich S; Howard M; Harmsen A; Randall TD; Lund FE. 2001. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med 7(11):1209-16. [PubMed: 11689885]  [MGI Ref ID J:126192]

Partida-Sanchez S; Goodrich S; Kusser K; Oppenheimer N; Randall TD; Lund FE. 2004. Regulation of dendritic cell trafficking by the ADP-ribosyl cyclase CD38: impact on the development of humoral immunity. Immunity 20(3):279-91. [PubMed: 15030772]  [MGI Ref ID J:89773]

Rodriguez-Alba JC; Moreno-Garcia ME; Sandoval-Montes C; Rosales-Garcia VH; Santos-Argumedo L. 2008. CD38 induces differentiation of immature transitional 2 B lymphocytes in the spleen. Blood 111(7):3644-52. [PubMed: 18223169]  [MGI Ref ID J:133536]

Shi G; Partida-Sanchez S; Misra RS; Tighe M; Borchers MT; Lee JJ; Simon MI; Lund FE. 2007. Identification of an alternative G{alpha}q-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes. J Exp Med 204(11):2705-18. [PubMed: 17938235]  [MGI Ref ID J:126146]

Sun L; Iqbal J; Dolgilevich S; Yuen T; Wu XB; Moonga BS; Adebanjo OA; Bevis PJ; Lund F; Huang CL; Blair HC; Abe E; Zaidi M. 2003. Disordered osteoclast formation and function in a CD38 (ADP-ribosyl cyclase)-deficient mouse establishes an essential role for CD38 in bone resorption. FASEB J 17(3):369-75. [PubMed: 12631576]  [MGI Ref ID J:82191]

Young GS; Choleris E; Lund FE; Kirkland JB. 2006. Decreased cADPR and increased NAD+ in the Cd38-/- mouse. Biochem Biophys Res Commun 346(1):188-92. [PubMed: 16750163]  [MGI Ref ID J:110441]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	The accelerated diabetes development in NOD.129P2(B6)-Cd38tm1Lnd/LtJ homozygous breeding stock is not significantly retarded by either CFA or alpha galactosylceramide prophylaxis.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryopreserved Embryos This strain is also available as cryopreserved embryos from our Repository. Orders for cryopreserved embryos are supplied subject to a signed agreement that must be returned to the Customer Service Department after order placement. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos from our repository, please visit our Cryopreserved Embryos web page. Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Type 1 Diabetes Repository collection.

Control Information

	Control
	001976 NOD/ShiLtJ
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.

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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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