| Research Abstract |
During mammalian neural development, a wide variety of neurons differentiates from relatively uniform common precursor cells. It is known that cell-cell interaction is essential to generate the neuronal type diversity ; Differentiating neurons inhibit the neighboring cells from differentiating into the same neuronal types (lateral inhibition). While the transmembrane protein Notch is involved in the lateral inhibition process, the intracellular pathway of manunalian Notch remains very elusive.
Recently, we and others found that the promoter activity of the bHLH genes Hes1 and Hes5 was induced by activation of Notch. Thus, to understand the mammalian Notch pathway, the role of Hes1 and Hes5 was examined by retrovirally misexpressing the constitutively active form of Notch (caNotch) in neural precursor cells prepared from wild-type, Hes1-null, Hes5-null, and Hes1-Hes5 double-null mouse embryos. We found that caNotch, which induced the endogenous Hes1 and Hes5 expression, inhibited neuronal differentiation in the wild-type, Hes1 -null, and Hes5-nulI background but not in the Hes1 -Hes5 double-null background. These results demonstrate that Hes1 and Hes5 are essential Notch effectors in regulation of mammalian neuronal differentiation and that the two Hesgenes conpensate each other downstream of Notch. We previously showed that Hes] inhibits neuronal differentiation by antagonizing the bHLH-type neuronal determination/differentiation gene Mash1.
Taken together, these data indicate that mammalian neuronal differentiation is regulated by the pathway "Notch * Hes1/Hes5 * Mash1 * neuronal differentiation" (*, activation ; * , inhibition).
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