The activation-induced cytidine deaminase (AID) gene, specifically expressed in germinal center B cells in mice, is a member of the cytidine deaminase family. We herein report mutations in the human counterpart of AID in patients with the autosomal recessive form of hyper-IgM syndrome (HIGM2). Three major abnormalities characterize AID deficiency: (1) the absence of immunoglobulin class switch recombination, (2) the lack of immunoglobulin somatic hypermutations, and (3) lymph node hyperplasia caused by the presence of giant germinal centers. The phenotype observed in HIGM2 patients (and in AID-/- mice) demonstrates the absolute requirement for AID in several crucial steps of B cell terminal differentiation necessary for efficient antibody responses.

Activation-induced cytidine deaminase (AID) is required for both CSR and SHM because AID deficiency in mouse and human completely abolishes these two genetic alterations (2, 3). In addition to AID, CSR and SHM require transcription of target DNAs, S regions, and V regions, respectively (4-10). AID expression in non-B cells such as fibroblasts and T cells can induce CSR and SHM on transfected artificial constructs if the target DNA is actively transcribed (11-13). Therefore, AID and target transcription appear to be essential and sufficient for CSR and SHM in non-B as well as B cells. However, studies on transgenic (Tg) mouse lines ubiquitously expressing AID showed neither distortion of the B220 ϩ B cell population nor increase in serum IgG levels (14). Although all mice died by 80 weeks because of T cell lymphomas, no B cell lymphomas were observed in the Tg mice (14). These observations have raised a possibility that Tg AID is negatively regulated in B cells. However, we could not exclude the possibility that dysregulation of T cells by a very early onset of T lymphomas may perturb B cell responses in AID-Tg mice.It is therefore important to test the effects of constitutive AID expression in B cells using a more defined system. We thus generated Tg mice, which express AID constitutively only in B cells, and crossed them with AID-deficient mice. Using this system, we found that the Tg AID, despite its abundance, is much less efficient for CSR and SHM than the endogenous AID, suggesting that AID is negatively regulated in B cells.

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: Sp6 is a member of the Sp family of transcription factors that regulate a wide range of cellular functions, such as cell growth and differentiation. Sp6, also called epiprofin, is specifically expressed in tooth germ, limb bud, and hair follicle, but there is little information on its function.To investigate the possible role of Sp6 in tooth development, first we established an Sp6-overproducing clone, CHA9, and analyzed the features of the cell, including cell proliferation and gene expression. The parental cells of CHA9 are the ameloblast-lineage G5 cells that we previously established from rat dental epithelia of lower incisor. Sp6 overproduction accelerated cell proliferation and induced the expression of ameloblastin mRNA, a marker of ameloblast differentiation. Second, we performed genome-wide screening of Sp6 target genes by microarray analysis. Out of a total 20,450 genes, 448 genes were up-regulated and 500 genes were down-regulated by Sp6. We found the expression of follistatin, a BMP antagonist, to be 22.4-fold lower in CHA9 than in control cells. Transfection of the Sp6-antisense construct into CHA9 cells restored follistatin expression back to equivalent levels seen in control cells, indicating that Sp6 regulates follistatin gene expression in ameloblasts.Our findings demonstrate that the follistatin gene is one of the Sp6 target genes in ameloblasts and suggest that Sp6 promotes amelogenesis through inhibition of follistatin gene expression. J. Med. Invest. 55 : 87-98, February, 2008

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We have isolated a novel gene that encodes a protein sharing significant similarity with myeloid antigen CD33. The complete cDNA contains an open reading frame of 1,326 nucleotides encoding 442 amino acids. The deduced amino acid sequence indicates that this molecule belongs to the immunoglobulin (1g) superfamily and is likely to be a new member of the sialoadhesin sub-family. It is composed of three 1g-like domains; its high degree of similarity to CD33 (70% identity) in the first and second of these domains implies that the placenta-specific gene product is likely to be associated with cell-cell interaction. Northern-blot analysis revealed transcripts of four distinct sizes, 7.5 kb, 5.0 kb, 4.1 kb, and 2.0 kb, specifically in the placenta. Consequently, we termed this gene CD33L (CD33 antigen-like). An alternatively-spliced transcript encoding a 342-amino-acid peptide which lacked the transmembrane region and the cytoplasmic tail was also isolated. We mapped CD33L by fluorescence in situ hybridization (FISH) to human chromosome 19q13.3, where the CD33 gene is also located.

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