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First published online 26 November 2003
doi: 10.1242/dev.00877
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1 Head Organizer Project, Vertebrate Body Plan Group, RIKEN Center for
Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku, Kobe, Hyougo
650-0047, Japan
2 Department of Morphogenesis, Institute of Molecular Embryology and Genetics,
Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
3 Division of Transgenic Technology, Center for Animal Resources and
Development, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
4 The Center for Tsukuba Advanced Research Alliance and Institute of Basic
Medical Sciences, University of Tsukuba, Tsukuba 305-8577, Japan
5 Nutrition Division, National Research Institute of Aquaculture, Fisheries
Research Agency, Nansei-cho, Watarai-gun, Mie 516-0193, Japan
6 Animal Resources and Genetic Engineering Team and Vertebrate Body Plan Group,
RIKEN Center for Developmental Biology, 2-2-3 Minatojima Minami Cho, Chuou-Ku,
Kobe, Hyougo 650-0047, Japan
* Author for correspondence (e-mail: isao{at}cdb.riken.go.jp)
Accepted 23 September 2003
The Otx2 gene, containing a highly conserved paired-type homeobox, plays a pivotal role in the development of the rostral head throughout vertebrates. Precise regulation of the temporal and spatial expression of Otx2 is likely to be crucial for proper head specification. However, regulatory mechanisms of Otx2 expression remain largely unknown. In this study, the Otx2 genome of the puffer fish Fugu rubripes, which has been proposed as a model vertebrate owing to its highly compact genome, was cloned. Consistently, Fugu Otx2 possesses introns threefold smaller in size than those of the mouse Otx2 gene. Otx2 mRNA was transcribed after MBT, and expressed in the rostral head region throughout the segmentation and pharyngula periods of wild-type Fugu embryos. To elucidate regulatory mechanisms of Otx2 expression, the expression of Otx2-lacZ reporter genes nearly covering the Fugu Otx2 locus, from –30.5 to +38.5 kb, was analyzed, by generating transgenic mice. Subsequently, seven independent cis-regulators were identified over an expanse of 60 kb; these regulators are involved in the mediation of spatiotemporally distinct subdomains of Otx2 expression. Additionally, these expression domains appear to coincide with local signaling centers and developing sense organs. Interestingly, most domains do not overlap with one another, which implies that cis-regulators for redundant expression may be abolished exclusively in the pufferfish so as to reduce its genome size. Moreover, these cis-regions were also able to direct expression in zebrafish embryos equivalent to that observed in transgenic mice. Further comparative sequence analysis of mouse and pufferfish intergenic regions revealed eight highly conserved elements within these cis-regulators. Therefore, we propose that, in vertebrate evolution, the Otx2 promoter acquires multiple, spatiotemporally specific cis-regulators in order to precisely control highly coordinated processes in head development.
Key words: Homeobox, Otx2, Pufferfish, Gene regulation, cis-region, Brain development, Evolution, Local signaling center
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