NOD.129S2(B6)-Casp1^tm1Sesh Casp4^del/LtJ

Stock number: 004947
Product name: ICE
Strain synonyms: NOD.Casp-1^null
Research areas: Diabetes and Obesity Research, Immunology, Inflammation and Autoimmunity Research, Research Tools

Description

Cultured LPS stimulated bone marrow derived macrophages from homozygous animals secrete less IL1 beta and IL1 alpha; IL18 is undetectable when compared with hemizygous and wild-type controls. Diabetes frequency of Casp1^tm1Sesh deficient animals is equivalent to NOD/Lt, heterozygote and wild-type controls. This strain is a useful model for studying the role of IL1 and IL18 cytokines in inflammatory processes relating to diabetes.

Detailed description

Casp1^tm1Sesh homozygous mice are viable, fertile, normal in size, and do not display any gross physical or behavioral abnormalities. There is no detectable expression of Casp1 in spleen by northern blot analysis or by RT-PCR of peritoneal exudate cells, brain, lung, heart, liver, adrenal gland, kidney, testis, and thymus (Li et al, 1995). Cultured LPS stimulated bone marrow derived macrophages from homozygous NOD.129S2(B6)- Casp1^tm1Sesh /LtJ animals secrete 4-fold less IL1 beta, 30% less IL1 alpha, and IL18 is undetectable when compared with hemizygous and wild-type controls. Diabetes frequency of Casp1^tm1Sesh deficient animals is equivalent to NOD/Lt, heterozygote and wild-type controls. Weanling Casp1^tm1Sesh homozygous animals injected with Complete Freund's adjuvant and young pre-diabetic males treated with multiple low dose streptozotocin behave similarly to control (wild type, heterozygote, or NOD/Lt) animals (Schott et al, 2004). NOD.129S2(B6)- Casp1^tm1Sesh/LtJ is a useful model for studying the role of IL1 and IL18 cytokines in inflammatory processes relating to diabetes.

Development

A construct containing a neomycin expression cassette inserted into exon 6 of Casp1 (cloned from a 129/Sv mouse), deleting 31 bp of sequence encoding the region of the catalytic active site and rendering the sequence out of frame after the insertion, was transfected into D3 (129S2/SvPas derived) embryonic stem cells (ES cells). These ES cells were injected into C57BL/6 blastocysts. Chimeric founders were initially mated to C57BL/6 and subsequently intercrossed to generate homozygotes (Li et al, 1995). In 1998, Dr. Edward Leiter at The Jackson Laboratory received B6.129S2-Casp1^tm1Sesh mice from Dr. Winnie Wong, BASF Bioresearch Corporation and backcrossed this mutation to NOD/Lt for 10 generations, subsequently intercrossing to generate homozygotes (Schott et al. 2004). In 2004, NOD.129S2(B6)- Casp1^tm1Sesh /LtJ homozygous strain at N10F11 was transferred from Edward Leiter's research colony to a Jackson Laboratory distribution colony.

Allele

Symbol: Casp1^tm1Sesh
Name: targeted mutation 1, Tara Seshadri
MGI accession ID: MGI:1927822
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Casp1
Marker name: caspase 1
Chromosome: 9
Strain of origin: 129S2/SvPas
Molecular note: A neomycin expression cassette was inserted into exon 6, deleting 31 bp of sequence encoding the region of the active site and rendering the sequence out of frame after the insertion. Northern blot analysis on spleen RNA demonstrated an absence of the normal transcript in homozygous mice, and western blot analysis showed that the protein was not expressed in peritoneal macrophages of homozygous mice. This allele was generated in ES cells that lack protein expression of Casp11 (Casp^129mt).
General note: The ES cells used to generate this allele contain the linked Casp4^del truncated allele that fails to produce a functional Casp4. Phenotypes associated with this allele may be affected by the presence of the Casp^del allele. J:193522

Allele

Symbol: Casp4^del
Name: deletion
MGI accession ID: MGI:5473345
Generation method: Spontaneous
Attributes: Null/Knockout
Marker symbol: Casp4
Marker name: caspase 4, apoptosis-related cysteine peptidase
Chromosome: 9
Strain of origin: 129P3/J and 129S1/SvImJ and 129S2/SvPas and 129S6/SvEvTac and 129X1/SvJ
Molecular note: RT-PCR confirmed that five 129 substrains (129X1/SvJ, 129S1/SvImJ, 129S2/SvPas, 129S6/SvEvTac and 129P3/J) express a transcript that lacks exon 7 (delta110 isoform). Sequencing identified a 5 bp deletion in exon 7 that results in the fusion of exon 6 and 8, a frame-shift after proline 304 and a stop codon after 5 aberrant amino acids. This deletion is not present in C57BL/6. Western blot analysis confirmed the absence of protein expression in LPS-primed macrophage.