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Zebrafish ( Danio rerio) has become an increasingly important model for immunological study. Its immune system is remarkably similar to that of mammals and includes both the adaptive and innate branches. Zebrafish T cells express functional T cell receptors (TCR), and all four TCR loci are present within the genome. Using 5′-rapid amplification of cDNA ends, we cloned and sequenced zebrafish TCRβ transcripts. TCRβ VDJ coding joints demonstrate conservation of mechanisms used by other vertebrate species to increase junctional diversity. Using the sequences obtained, along with previously published data, we comprehensively annotated the zebrafish TCRβ locus. Overall, organization of the locus resembles that seen in mammals. There are 51 V segments, a single D segment, 27 Jβ1 segments, a single Jβ2 segment, and two constant regions. This description of the zebrafish TCRβ locus has the potential to enhance immunological research in zebrafish and further our understanding of mammalian TCR repertoire generation. [ABSTRACT FROM AUTHOR]

Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krev1 interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Krit1. PDCD10 bound to germinal center kinase III (GCKIII) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcd10 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity. [ABSTRACT FROM AUTHOR]