| Budget Amount *help |
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2002: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2001: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2000: ¥4,600,000 (Direct Cost: ¥4,600,000)
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| Research Abstract |
Neural development consists of three major steps: (1) maintenance of neural stem cells, (2) neurogenesis and (3) gliogenesis. We elucidated the transcription factors that regulate these steps.
A. Maintenance of neural stem cells and gliogenesis
Hesl and Hes5, mammalian bHLH genes are expressed by neural stem cell and differentiating glia. Cells infected with Hesl- and Hes5-transducing retrovirus remained as neural stem cells or became glia but did not differentiate into neurons. Conversely, in mice mutant for Herl and Hes5, maintenance of neural stem cells was impaired and, as a result, neurons differentiated prematurely, resulting in severe defects of the brain morphogenesis. Thus, Hesl and Hes5 play important roles both in maintenance of neural stem cells and in gliogenesis. We also found that expression of both Hesl mRNA and protein oscillates in a 2-hour periodicity. This oscillation occurs autonomously and depends on the negative feedback of Hesl, which represses its own expression. Thus, Hesl acts as a 2-hour cycle biological clock. Hesl oscillation may be involved in the selection between remaining as stem cells and differentiating into neurons.
B. Neurogenesis
Two bHLH genes Mash1 and Math3, are co-expressed by many differentiating neurons. Misexpression of Mash1 and Math3 promoted the neuronal fate determination at the expense of the glial fate. Conversely, in mice double-mutant for Mash1 and Math3, many neurons were missing and, instead, those cells that normally differentiate into neurons adopted the glial fate. These results indicate that Mash1 and Math3 direct neuronal versus glial fate determination. However, bHLH genes alone are not sufficient but combinations with homeobox genes are important for generation of the neuronal diversity.
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