The mammalian nod genes encode proteins that have been implicated in the pathogenesis of immune-mediated diseases, including inflammatory bowel disease (ibd), graft-versus-host disease and uveitis (hugot et al., 2001; ogura et al., 2001; rosenbaum et al., 2003; holler et al., 2004; brenmoehl et al., 2007). ibd is thought to arise through aberrant host-microbe interactions involving innate and adaptive immune signaling pathways. genetic susceptibility loci for the major forms of ibd (crohn’s disease and ulcerative colitis) include components of the innate immune system (mathew, 2008). the larval zebrafish ( danio rerio ) is an established model for the investigation of in vivo innate immunity (trede et al., 2004). nod2 (nucleotide oligomerization domain 2) was the first gene linked to ibd (hugot et al., 2001; ogura et al., 2001) and is the locus most strongly linked to the disorder. our laboratory has analyzed the zebrafish nod orthologs to explore the use of this model in understanding aspects of ibd genetics. mammalian nod proteins share a common domain arrangement of a ligand-binding leucine-rich repeat domain, a central nucleotide oligomerization domain and an effector n- terminal caspase recruitment domain (card), with nod2 having two cards. nod proteins function as cytosolic microbial pattern recognition molecules and share many facets of form and function with the ancient family of plant disease resistance proteins (litman et al., 2005; ting et al., 2008; sabbah et al., 2009). zebrafish orthologs of nod1 and have been identified from the zebrafish genome, and it was found that these genes have conserved genetic synteny and the predicted proteins have identical domain structure to those of mammalian proteins (laing et al., 2008; chang et al., 2010). however, whether the biological roles of zebrafish and human nods are similar has not been determined. studies have explored the genomic evolution and tissue expression of the zebrafish nod orthologs in adults, but have not investigated expression or function of zebrafish nods in larvae (stein et al., 2007; laing et al., 2008; chang et al., 2010). to successfully apply the genetically amenable zebrafish platform to the study of complex immune-mediated disease, a broader understanding of zebrafish immunogenetics is required. several studies have characterized zebrafish orthologs of many important mammalian cytokines, including members of the interleukin, interferon and tumor necrosis factor cytokine families (pressley et al., 2005; clay et al., 2008; lu et al., 2008; sieger et al., 2009; oehlers et al., 2010). however, fewer in vivo studies have been carried out to examine the conservation of pattern recognition molecule function in zebrafish. investigation into toll-like receptor 4 (tlr4) signaling in zebrafish has revealed that zebrafish tlr4 functions as a non-lipopolysaccharide-sensing negative regulator of nf k b activation, whereas mammalian tlr4 functions as a lipopolysaccharide-sensing positive regulator of nf b activation (fan et al., 2008; sepulcre et al., 2009; sullivan et al., 2009). conversely, undefined signaling through the tlr adaptor molecule myd88 seems to have a conserved antimicrobial function in zebrafish (van der sar et al., 2006; hall et al., 2009). furthermore, zebrafish myd88 controls the evolutionarily conserved