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First published online 16 June 2004
doi: 10.1242/dev.01220

Development 131, 3319-3331 (2004)
Published by The Company of Biologists 2004
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Regulation of Otx2 expression and its functions in mouse forebrain and midbrain

Daisuke Kurokawa1, Hiroshi Kiyonari2, Rika Nakayama2, Chiharu Kimura-Yoshida1, Isao Matsuo1 and Shinichi Aizawa1,2,*

1 Laboratory for Vertebrate Body Plan, Center for Developmental Biology (CDB), RIKEN Kobe, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0046, Japan
2 Laboratory for Animal Resources and Genetic Engineering, Center for Developmental Biology (CDB), RIKEN Kobe, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0046, Japan

* Author for correspondence (e-mail saizawa{at}cdb.riken.jp)

Accepted 8 April 2004

Otx2 expression in the forebrain and midbrain was found to be regulated by two distinct enhancers (FM and FM2) located at 75 kb 5' upstream and 115 kb 3' downstream. The activities of these two enhancers were absent in anterior neuroectoderm earlier than E8.0; however, at E9.5 their regions of activity spanned the entire mesencephalon and diencephalon with their caudal limits at the boundary with the metencephalon or isthmus. In telencephalon, activities were found only in the dorsomedial aspect. Potential binding sites of OTX and TCF were essential to FM activity, and TCF sites were also essential to FM2 activity. The FM2 enhancer appears to be unique to rodent; however, the FM enhancer region is deeply conserved in gnathostomes. Studies of mutants lacking FM or FM2 enhancer demonstrated that these enhancers indeed regulate Otx2 expression in forebrain and midbrain. Development of mesencephalic and diencephalic regions was differentially regulated in a dose-dependent manner by the cooperation between Otx1 and Otx2 under FM and FM2 enhancers: the more caudal the structure the higher the OTX dose requirement. At E10.5 Otx1–/–Otx2{Delta}FM/{Delta}FM mutants, in which Otx2 expression under the FM2 enhancer remained, exhibited almost complete loss of the entire diencephalon and mesencephalon; the telencephalon did, however, develop.

Key words: Otx2, Otx1, Enhancer, Forebrain, Midbrain, Anterior neuroectoderm, WNT signaling, Mouse


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