Summary of Research Project Results under JSPS FY2002
"Research for the Future Program"

1.Research Institution Kyoto University
2.Research Area Life Sciences
3.Research Field Regulation Networks of Eukaryotic Gene Expression
4.Term of Project FY 1998 - FY 2002
5.Project Number 98L01103
6.Title of Project Regulation of Gene Expression in the Nervous System

7.Project Leader
Name Institution,Department Title of Position
Ryoichiro, Kageyama Kyoto University, Institute for Virus Research Professor

8.Core Members

Name Institution,Department Title of Position
Masayuki, Masu University of Tsukuba, Institute of Basic Medical Sciences Professor

9.Summary of Research Results

We have examined the transcriptional mechanism for neural development. We have characterized (I) transcription factors for neural development and (II) regulation of neural gene expression. The results will be useful for regeneration of the neural tissues.
(I) Transcription factors for neural development
Neural development consists of three major steps: (1) maintenance of neural stem cells, (2) neurogenesis and (3) gliogenesis. We have analyzed the transcription factors that regulate these steps and found that bHLH factors play major roles in neural development.
(1) Maintenance of neural stem cells
The bHLH factors Hes1 and Hes5 are expressed by neural stem cells. Overexpression of the factors maintains neural stem cells while, in the absence of Hes1 and Hes5, neural stem cells are not properly maintained and prematurely differentiate into neurons. Thus, Hes1 and Hes5 play an essential role in maintenance of neural stem cells.
(2) Neurogenesis
The bHLH factors Mash1 and Math3 are expressed by differentiating neurons. Overexpression of the factors promotes neurogenesis while, in the absence of Mash1 and Math3, cells are inhibited from neuronal differentiation and exhibit a fate switch to glia. These results indicate that Mash1 and Math3 direct neuronal versus glial fate determination.
(3) Gliogenesis
The bHLH factors Hes1, Hes5 and Hesr2 are expressed by differentiating glia, and overexpression of the factors in the postnatal retina promotes gliogenesis. This activity may reflect the gliogenic phenotypes of Mash1-Math3 double knock-out mice because Hes1, Hes5 and Hesr2 are capable of antagonizing Mash1 and Math3.
(II) Regulation of neural gene expression
The 12-kb promoter of the neural gene SulfFP1 drives its expression in the bone, kidney, and brain. In zebrafish, sonic hedgehog overexpression increased SulfFP1/2 expression in the brain, whereas blockage of sonic hedgehog signalling resulted in the decrease of the SulfFP1/2 expression in the brain and the increase of SulfFP1 expression in the somite. These results indicate that SulfFP expression is controlled by several signalling systems in a tissue-dependent manner.

10.Key Words
(1)bHLH factor   (2)fate determination   (3)differentiation
(4)Hes   (5)gliogenesis   (6)neural patterning
(7)neural stem cell   (8)neurogenesis   (9)sonic hedgehog