|Budget Amount *help
¥15,200,000 (Direct Cost : ¥15,200,000)
Fiscal Year 1999 : ¥4,800,000 (Direct Cost : ¥4,800,000)
Fiscal Year 1998 : ¥4,900,000 (Direct Cost : ¥4,900,000)
Fiscal Year 1997 : ¥5,500,000 (Direct Cost : ¥5,500,000)
In mammalian neural development, initially neural precursor cells are maintained but later they differentiate into neurons and glial cells that form a complex nervous system. To elucidate the intracellular mechanism for neural development, we focused on bHLH genes and characterized their functions. Since the membrane protein Notch, which is known to maintain neural precursors, induced expression of the inhibitory bHLH genes Hes1 and Hes5, functions of these bHLH genes in neural precursor cells were first determined by expressing the active form of Notch in cells prepared from Hes1-null, Hes5-null, and Hes1-Hes5 double-null mouse embryos. Whereas Notch still inhibited differentiation in the absence of either Hes1 or Hes5, it did not in the absence of both Hes1 and Hes5 as essential Notch effectors. Thus, Notch-Hes pathway plays an important role in maintenance of neural precursor cells at early stages of development. At later stages of neural development, Hes5 was expressed by differentiating glial cells. Misexpression of Hes5 in the developing retina specifically induced gliogenesis and conversely glial cell number was reduced in Hes5-deficient retina. In contrast, Hes1 inhibited both neuronal and glial cell development and maintained neural precursor cells even at later stages. Neuronal bHLH genes such as Math3 and Mash1 promoted neurogenesis but inhibited gliogenesis. Thus, bHLH genes regulate all the cell fate, remaining as precursors (Hes1, Hes5) and differentiating into neurons (Math3, Mash1) or glial cells (Hes5), and the balance of these bHLH genes may be important for the timing of differentiation and the ratios of neurons versus glial cells.