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J. Biol. Chem., Vol. 279, Issue 27, 28492-28498, July 2, 2004

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Requirement of Multiple Basic Helix-Loop-Helix Genes for Retinal Neuronal Subtype Specification^*

Tadamichi Akagi, Tomoyuki Inoue, Goichi Miyoshi, Yasumasa Bessho, Masayo Takahashi¶, Jacqueline E. Lee||, François Guillemot**, and Ryoichiro Kageyama

From the Institute for Virus Research, Kyoto University, the Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, and the ^¶Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan, the ^||Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Colorado 80309, and the ^**National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

Retinal precursor cells give rise to six types of neurons and one type of glial cell during development, and this process is controlled by multiple basic helix-loop-helix (bHLH) genes. However, the precise mechanism for specification of retinal neuronal subtypes, particularly horizontal neurons and photoreceptors, remains to be determined. Here, we examined retinas with three different combinations of triple bHLH gene mutations. In retinas lacking the bHLH genes Ngn2, Math3, and NeuroD, horizontal neurons as well as other neurons such as bipolar cells were severely decreased in number. In the retina lacking the bHLH genes Mash1, Ngn2, and Math3, horizontal and other neurons were severely decreased, whereas ganglion cells were increased. In the retina lacking the bHLH genes Mash1, Math3, and NeuroD, photoreceptors were severely decreased, whereas ganglion cells were increased. In all cases, glial cells were increased. The increase and decrease of these cells were the result of cell fate changes and cell death and seem to be partly attributable to the remaining bHLH gene expression, which also changes because of triple bHLH gene mutations. These results indicate that multiple bHLH genes cross-regulate each other, cooperatively specify neuronal subtypes, and regulate neuronal survival in the developing retina.

Received for publication, January 26, 2004 , and in revised form, April 19, 2004.

^* This work was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Society for the Promotion of Science. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Inst. for Virus Research, Kyoto University, Shogoin-Kawahara, Sakyo-ku, Kyoto 606-8507, Japan. Tel.: 81-75-751-4011; Fax: 81-75-751-4807; E-mail: rkageyam{at}virus.kyoto-u.ac.jp.

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