| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Research Abstract |
B cell-specific mutation of Pten in mice showed elevated numbers of B1a cells and increased serum autoantibodies. Among B2 cells in the mutant spleens, numbers of marginal zone B (MZB) cells were significantly increased while those of follicular B (FOB) cells were correspondingly decreased. Pten-deficient B cells hyperproliferated, were resistant to apoptotic stimuli, and showed enhanced migration. In addition, immunoglobulin class switch recombination was defective and induction of activation-induced cytidine deaminase (AID) was impaired. Thus, Pten plays a role in developmental fate determination of B cells and is an indispensable regulator of B cell homeostasis.
Keratinocyte-specific null mutation of Pten in mice exhibit wrinkled skin because of epidermal hyperplasia and hyperkeratosis and ruffled, shaggy, and curly hair. Histological examination revealed that skin morphogenesis is accelerated in the mutant mice. Within 3 weeks of birth, 90% of k5Ptenflox/flox mice die of malnutritio
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n possibly caused by hyperkeratosis of the esophagus. All mutant mice develop spontaneous tumors within 8.5 months of birth, and chemical treatment accelerates the onset of tumors. The mutant keratinocytes are hyperproliferative and resistant to apoptosis and show increased activation of the Pten downstream signaling mediators. Pten is thus an important regulator of normal development and oncogenesis in the skin.
To elucidate the intracellular signaling mechanisms that underlie germ cell differentiation and proliferation, we have generated mice with a PGC-specific deletion of the Pten gene. Male mice that lacked PTEN exhibited bilateral testicular teratoma, which resulted from impaired mitotic arrest and outgrowth of cells with immature characters. Experiments with PTEN-null PGCs in culture revealed that these cells had greater proliferative capacity and enhanced pluripotent embryonic germ (EG) cell colony formation. PTEN appears to be essential for germ cell differentiation and an important factor in testicular germ cell tumor formation. Less
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