Smad4-Shh-Nfic signaling cascade-mediated epithelial-mesenchymal interaction is crucial in regulating tooth root development.

Transforming growth factor beta (TGF-beta)/bone morphogenetic protein (BMP) signaling is crucial for regulating epithelial-mesenchymal interaction during organogenesis, and the canonical Smad pathway-mediated TGF-beta/BMP signaling plays important roles during development and disease. During tooth development, dental epithelial cells, known as Hertwig's epithelial root sheath (HERS), participate in root formation following crown development. However, the functional significance of HERS in regulating root development remains unknown. In this study we investigated the signaling mechanism of Smad4, the common Smad for TGF-beta/BMP signaling, in HERS in regulating root development. Tissue-specific inactivation of Smad4 in HERS results in abnormal enamel and dentin formation in K14-Cre;Smad4(fl/fl) mice. HERS enlarges but cannot elongate to guide root development without Smad4. At the molecular level, Smad4-mediated TGF-beta/BMP signaling is required for Shh expression in HERS and Nfic (nuclear factor Ic) expression in the cranial neural crest (CNC)-derived dental mesenchyme. Nfic is crucial for root development, and loss of Nfic results in a CNC-derived dentin defect similar to the one of K14-Cre;Smad4(fl/fl) mice. Significantly, we show that ectopic Shh induces Nfic expression in dental mesenchyme and partially rescues root development in K14-Cre;Smad4(fl/fl) mice. Taken together, our study has revealed an important signaling mechanism in which TGF-beta/BMP signaling relies on a Smad-dependent mechanism in regulating Nfic expression via Shh signaling to control root development. The interaction between HERS and the CNC-derived dental mesenchyme may guide the size, shape, and number of tooth roots.

Elevated expression of activation induced cytidine deaminase in peripheral blood mononuclear cells precedes AIDS-NHL diagnosis.

Non-Hodgkin's B cell lymphoma (NHL) is a common cancer in HIV infection. Many NHL are thought to result from errors in class switch recombination and/or somatic hypermutation, processes that occur in germinal center B cells, and require the activity of activation induced cytidine deaminase (AID). Since NHL is a common cancer in HIV infection, and expression of AID could contribute to the development of NHL, we hypothesized that AID expression would be elevated in those who went on to develop AIDS-associated NHL (AIDS-NHL). AID mRNA levels were measured by TaqMan RT-PCR in peripheral blood mononuclear cells, obtained prior to AIDS-NHL diagnosis, from 16 HIV-infected subjects who developed AIDS-NHL, and from control subjects (AIDS but no NHL, and HIV-negative subjects). PBMC AID expression was markedly elevated in those who developed AIDS-NHL, when compared to AIDS and HIV-negative controls. Additionally, AID expression was seen to differ depending on NHL subtype, with the highest levels of expression seen in those who developed Burkitt's lymphoma.

Infection of human B cells with Epstein-Barr virus results in the expression of somatic hypermutation-inducing molecules and in the accrual of oncogene mutations.

Infection of human B cells with Epstein-Barr virus (EBV) was seen to result in activation-induced cytidine deaminase (AID) and polymerase-eta (pol-eta) gene expression. AID and pol-eta are cellular gene products that play central roles in the DNA-modifying processes involved in immunoglobulin gene class switch recombination and somatic hypermutation. Errors in these processes can result in oncogene mutation/translocation, thereby contributing to lymphomagenesis. It was seen that EBV infected, AID, and pol-eta expressing B cells accumulated mutations in cellular proto-oncogenes (BCL-6 and p53) that are known to be involved in the genesis of B cell lymphoma. The nature of the mutations seen in these oncogenes was consistent with the known activity of AID and pol-eta. These findings indicate that EBV induced AID and pol-eta expression, and that this was associated with oncogene mutation, providing a novel means by which EBV infection of B cells may contribute to lymphomagenesis.