Possível envolvimento de SINEs na formação específica de cérebros de mamíferos

Possible involvement of SINEs in mammalian-specific brain formation

1. Takeshi Sasaki*, 
2. Hidenori Nishihara*, 
3. Mika Hirakawa^†, 
4. Koji Fujimura*,
5. Mikiko Tanaka*, 
6. Nobuhiro Kokubo*, 
7. Chiharu Kimura-Yoshida^‡,
8. Isao Matsuo^‡, 
9. Kenta Sumiyama^§, 
10. Naruya Saitou^§, 
11. Tomomi Shimogori^¶, and 
12. Norihiro Okada*,^‖

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Author Affiliations

1. *Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259-B-21 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan;
2. ^†Bioinformatics Center, Institute for Chemical Research, Kyoto University, Gokasho, Uji, Kyoto 611-0011, Japan;
3. ^‡Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka Prefectural Hospital Organization, Izumi, Osaka 594-1101, Japan;
4. ^§National Institute of Genetics, Mishima, Shizuoka 411-8540, Japan; and
5. ^¶RIKEN Brain Science Institute, 2-1 Hirosawa Wako City, Saitama 351-0198, Japan

1. Edited by Wen-Hsiung Li, University of Chicago, Chicago, IL, and approved January 23, 2008 (received for review October 3, 2007)

Abstract

Retroposons, such as short interspersed elements (SINEs) and long interspersed elements (LINEs), are the major constituents of higher vertebrate genomes. Although there are many examples of retroposons' acquiring function, none has been implicated in the morphological innovations specific to a certain taxonomic group. We previously characterized a SINE family, AmnSINE1, members of which constitute a part of conserved noncoding elements (CNEs) in mammalian genomes. We proposed that this family acquired genomic functionality or was exapted after retropositioning in a mammalian ancestor. Here we identified 53 new AmnSINE1 loci and refined 124 total loci, two of which were further analyzed. Using a mouse enhancer assay, we demonstrate that one SINE locus, AS071, 178 kbp from the gene FGF8 (fibroblast growth factor 8), is an enhancer that recapitulates FGF8 expression in two regions of the developing forebrain, namely the diencephalon and the hypothalamus. Our gain-of-function analysis revealed that FGF8 expression in the diencephalon controls patterning of thalamic nuclei, which act as a relay center of the neocortex, suggesting a role for FGF8 in mammalian-specific forebrain patterning. Furthermore, we demonstrated that the locus, AS021, 392 kbp from the gene SATB2, controls gene expression in the lateral telencephalon, which is thought to be a signaling center during development. These results suggest important roles for SINEs in the development of the mammalian neuronal network, a part of which was initiated with the exaptation of AmnSINE1 in a common mammalian ancestor.

• conserved noncoding element
 
• enhancer
 
• evolution
 
• mouse

Footnotes

• ^‖To whom correspondence should be addressed. E-mail:nokada@bio.titech.ac.jp
• Author contributions: N.O. designed research; T. Sasaki, H.N., M.H., K.F., M.T., N.K., C.K.-Y., I.M., K.S., N.S., and T. Shimogori performed research; K.S. and N.S. contributed new reagents/analytic tools; T. Sasaki, M.H., K.F., M.T., N.K., C.K.-Y., and I.M. analyzed data; and T. Shimogori and N.O. wrote the paper.
• The authors declare no conflict of interest.
• This article is a PNAS Direct Submission.
• This article contains supporting information online at www.pnas.org/cgi/content/full/0709398105/DC1.
• Freely available online through the PNAS open access option.
• © 2008 by The National Academy of Sciences of the USA
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