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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.08.028 Byline: Yusuke Sakurai, Daisuke Kurokawa, Hiroshi Kiyonari, Eriko Kajikawa, Yoko Suda, Shinichi Aizawa Keywords: Otx2; Otx1; Enhancer; Forebrain; Midbrain; Isthmus Abstract: Otx2 is expressed in each step and site of head development. To dissect each Otx2 function we have identified a series of Otx2 enhancers. The Otx2 expression in the anterior neuroectoderm is regulated by the AN enhancer and the subsequent expression in forebrain and midbrain later than E8.5 by FM1 and FM2 enhancers; the Otx1 expression takes place at E8.0. In telencephalon later than E9.5 Otx1 continues to be expressed in the entire pallium, while the Otx2 expression is confined to the most medial pallium. To determine the Otx functions in forebrain and midbrain development we have generated mouse mutants that lack both FM1 and FM2 enhancers (DKO: Otx2.sup.[DELTA]FM1[DELTA]FM2/[DELTA]FM1[DELTA]FM2) and examined the TKO (Otx1.sup.-/- Otx2.sup.[DELTA]FM1[DELTA]FM2/[DELTA]FM1[DELTA]FM2) phenotype. The mutants develop normally until E8.0, but subsequently by E9.5 the diencephalon, including thalamic eminence and prethalamus, and the mesencephalon are caudalized into metencephalon consisting of isthmus and rhombomere 1; the caudalization does not extend to rhombomere 2 and more caudal rhombomeres. In rostral forebrain, neopallium, ganglionic eminences and hypothalamus in front of prethalamus develop; we propose that they become insensitive to the caudalization with the switch from the Otx2 expression under the AN enhancer to that under FM1 and FM2 enhancers. In contrast, the medial pallium requires Otx1 and Otx2 for its development later than E9.5, and the Otx2 expression in diencepalon and mesencephalon later than E9.5 is also directed by an enhancer other than FM1 and FM2 enhancers. Article History: Received 18 June 2010; Revised 24 August 2010; Accepted 25 August 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.03.013 Byline: Daisuke Kurokawa (a)(b), Tomomi Ohmura (a), Hajime Ogino (c), Masaki Takeuchi (a), Ai Inoue (a), Fumitaka Inoue (a), Yoko Suda (a), Shinichi Aizawa (a) Keywords: Otx2; Head organizer; Anterior visceral endoderm; Anterior mesendoderm; Cis-element; Evolution Abstract: In the mouse, the Otx2 gene has been shown to play essential roles in the visceral endoderm during anterior-posterior axis formation and head induction. While these are primary processes in vertebrate embryogenesis, the visceral endoderm is a tissue unique to mammals. Two enhancers (VE and CM) have been previously found to direct Otx2 expression during early embryogenesis. This study demonstrates that in anterior visceral endoderm the CM enhancer does not have an activity by itself, but enhances the activity of the VE enhancer. These two enhancers also cooperate for the activities in anterior mesendoderm and cephalic mesenchyme. Comparative studies suggest that VE enhancer function was most likely established before the divergence of sarcopterygians into Actinistia, Dipnoi and tetrapods, while the nucleotide sequence corresponding to the VE enhancer was already present in the last common ancestor of bony fishes. The CM enhancer sequence and function would have been also established in ancestral sarcopterygians. The VE/CM enhancers and their gene cascades in the ancestral sarcopterygian head organizer would then have been co-opted by amphibian deep endoderm cells and mammalian visceral endoderm cells for the head development. Author Affiliation: (a) Laboratory for Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, 2-2-3 Minatojima Minamimachi, Chuou-ku, Kobe 650-0047, Japan (b) Misaki Marine Biological Station, Graduate School of Science, The University of Tokyo, Miura 238-0225, Japan (c) Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Ikoma 630-0192, Japan Article History: Received 1 December 2009; Revised 15 March 2010; Accepted 16 March 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2008.09.018 Byline: Yoko Suda (a), Daisuke Kurokawa (a)(c), Masaki Takeuchi (a), Eriko Kajikawa (a), Shigeru Kuratani (b), Chris Amemiya (d), Shinichi Aizawa (a) Keywords: Otx; Fugu; Bichir; Skate; Lamprey; Head development; Organizer; Anterior mesendoderm; Anterior neuroectoderm; Brain Abstract: To assess evolutional changes in the expression pattern of Otx paralogues, expression analyses were undertaken in fugu, bichir, skate and lamprey. Together with those in model vertebrates, the comparison suggested that a gnathostome ancestor would have utilized all of Otx1, Otx2 and Otx5 paralogues in organizer and anterior mesendoderm for head development. In this animal, Otx1 and Otx2 would have also functioned in specification of the anterior neuroectoderm at presomite stage and subsequent development of forebrain/midbrain at somite stage, while Otx5 expression would have already been specialized in epiphysis and eyes. Otx1 and Otx2 functions in anterior neuroectoderm and brain of the gnathostome ancestor would have been differentially maintained by Otx1 in a basal actinopterygian and by Otx2 in a basal sarcopterygian. Otx5 expression in head organizer and anterior mesendoderm seems to have been lost in the teleost lineage after divergence of bichir, and also from the amniotes after divergence of amphibians as independent events. Otx1 expression was lost from the organizer in the tetrapod lineage. In contrast, in a teleost ancestor prior to whole genome duplication, Otx1 and Otx2 would have both been expressed in the dorsal margin of blastoderm, embryonic shield, anterior mesendoderm, anterior neuroectoderm and forebrain/midbrain, at respective stages of head development. Subsequent whole genome duplication and the following genome changes would have caused different Otx paralogue usages in each teleost lineage. Lampreys also have three Otx paralogues; their sequences are highly diverged from gnathostome cognates, but their expression pattern is well related to those of skate Otx cognates. Author Affiliation: (a) Laboratory for Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan (b) Evolutionary Morphology, Center for Developmental Biology, RIKEN Kobe, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan (c) Misaki Marine Biological Station, Graduate School of Science, The University of Tokyo, 1024 Koajiro, Misaki, Miura, Kanagawa 238-0225, Japan (d) Molecular Genetics Program, Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA Article History: Received 15 May 2008; Revised 10 September 2008; Accepted 12 September 2008