Congenic NOD/Lt mice homozygous for the Cd38tm1Lnd mutation (Commonly referred to as NOD.Cd38 short) 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.Cd38tm1Lnd mutant mice. Although CD38 is reportedly required for normal pancreatic beta cell responses to glucose, this was not confirmed in congenic, doubly homozygous NOD.PkrdcscidCD38tm1Lnd mutant mice.
NOD.129P2(B6)-Cd38tm1Lnd/LtJ mice are valuable for understanding how systemic NAD metabolism can be used to alter immunoregulatory networks.
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-Cd38tm1Lnd). B6.129P2-Cd38tm1Lnd/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)-Cd38tm1Lnd/LtJ at generation N11F5.
|Allele Name||targeted mutation 1, Frances E Lund|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||CD38-; CD38null|
|Gene Symbol and Name||Cd38, CD38 antigen|
|Gene Synonym(s)||ADPRC 1; ADPRC1; CD38 antigen, related sequence 1; Cd38-rs1; Cd38-rs1|
|Strain of Origin||129P2/OlaHsd|
|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.|
|Mutations Made By|| |
Debra Cockayne, Roche Bioscience
The accelerated diabetes development in NOD.129P2(B6)-Cd38tm1Lnd/LtJ homozygous breeding stock is not significantly retarded by either CFA or alpha galactosylceramide prophylaxis.
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