Skeletogenesis depends on the activity of bone-forming cells derived from mesenchymal cells. The pathways that control mesenchymal cell differentiation are not well understood. We propose that Foxo1 is an early molecular regulator during mesenchymal cell differentiation into osteoblasts. In mouse embryos, Foxo1 expression is higher in skeletal tissues, while Foxo1 silencing has a drastic impact on skeletogenesis and craniofacial development, specially affecting pre-maxilla, nasal bone, mandible, tibia, and clavicle. Similarly, Foxo1 activity and expression increase in mouse mesenchymal cells under the influence of osteogenic stimulants. In addition, silencing Foxo1 blocks the expression of osteogenic markers such as Runx2, alkaline phosphatase, and osteocalcin and results in decreased culture calcification even in the presence of strong osteogenic stimulants. Conversely, the expression of these markers increases significantly in response to Foxo1 overexpression. One mechanism through which Foxo1 affects mesenchymal cell differentiation into osteoblasts is through regulation of a key osteogenic transcription factor, Runx2. Indeed, our results show that Foxo1 directly interacts with the promoter of Runx2 and regulates its expression. Using a tibia organ culture model, we confirmed that silencing Foxo1 decreases the expression of Runx2 and impairs bone formation. Furthermore, our data reveals that Runx2 and Foxo1 interact with each other and cooperate in the transcriptional regulation of osteoblast markers. In conclusion, our in vitro, ex vivo, and in vivo results strongly support the notion that Foxo1 is an early molecular regulator in the differentiation of mesenchymal cells into osteoblast.Undifferentiated mesenchymal cells can differentiate into osteoblasts (bone-forming cells), adipocytes (fat cells), chondrocytes (cartilage cells), and myocytes (muscle cells) under the influence of various hormones and growth factors (1). Commitment and differentiation of mesenchymal cells into osteoblasts is crucial during skeletal development and bone growth.Whether mesenchymal cells differentiate along the osteogenic or other pathway depends on the activation of specific transcription factors. The importance of transcription factors in controlling skeletal development can be appreciated in the human skeletal disorder cleidocranial dysplasia. In this condition, deregulation of an important osteogenic transcription factor, Runx2, produces a striking phenotype with anterior fontanelle, hypoplasia or aplasia of the clavicle, wide pubic symphysis, and short stature (2).Although some of the transcription factors that control osteoblast differentiation are well characterized, the role of others remains unclear. One such factor is Foxo1 (forkhead box class O). Foxo1 belongs to the winged helix/forkhead family of transcription factors that is characterized by a 100-amino acid monomeric DNA-binding domain called the FOX domain. Other portions of the forkhead proteins, such as the DNA transactivation or DNA transrepression domains, a...

The prefrontal cortex has been implicated in schizophrenia (SZ) and affective disorders by gene expression studies. Owing to reciprocal connectivity, the thalamic nuclei and their cortical fields act as functional units. Altered thalamic gene expression would be expected to occur in association with cortical dysfunction. We screened the expression of the entire human genome of neurons harvested by laser-capture microdissection (LCM) from the thalamic primary relay to dorsolateral prefrontal cortex in three psychiatric disease states as compared with controls. Microarray analysis of gene expression showed the largest number of dysregulated genes was in SZ, followed by major depression (MD) and bipolar mood bipolar (BP) (1152, 385 and 288, respectively). Significantly, IGF1-mTOR-, AKT-, RAS-, VEGF-, Wnt-and immune-related signaling, eIF2-and proteasome-related genes were unique to SZ. Vitamin D receptor and calcium signaling pathway were unique to BP. AKAP95 pathway and pantothenate and CoA biosynthesis were unique to MD. There are significant differences among the three psychiatric disorders in MDNp cells. These findings offer new insights into the transcriptional dysregulation in the thalamus of SZ/BP/MD subjects.

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HLA class I molecules are recognized by CTL that eliminate virally infected and malignantly transformed cells presenting foreign peptide—a process termed immunosurveillance. Many tumors have reduced levels of membrane HLA class I. Tumor cells with mutations that reduce HLA class I avoid immunosurveillance and continue to proliferate. As tobacco use can induce tumors, we examined the effect of tobacco extracts on membrane HLA class I. These studies show that culture of cells in media containing tobacco extracts reduces membrane HLA class I, but not other proteins, on primary keratinocytes and other cell types. Culture in tobacco extracts, but not extracts of other substances, reduces TAP1 protein, but does not reduce expression of HLA class I H chain, L chain, or the housekeeping protein β-actin. The reduction of TAP1 protein occurs within 4 h and is dose-dependent. Culture in tobacco extracts reduces TAP1 protein abundance, but not steady-state mRNA abundance. Tobacco-treated cells show defects in HLA class I biosynthesis similar to those found in TAP1-deficient cell lines. Transfection with TAP1 cDNA restores TAP1 protein abundance, HLA class I biosynthesis, and cell surface expression. Combined, these data show that culture in tobacco extracts reduces TAP1 protein abundance and membrane HLA class I levels. Reduction in membrane HLA class I could permit subsequent malignant transformation of cells to be undetected by the immune system.