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First published online 4 July 2007
doi: 10.1242/dev.02870

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: dev.02870v1 134/15/2783    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Related articles in Development Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakatani, T. Articles by Ono, Y. Search for Related Content PubMed PubMed Citation Articles by Nakatani, T. Articles by Ono, Y.

Helt determines GABAergic over glutamatergic neuronal fate by repressing Ngn genes in the developing mesencephalon

Tomoya Nakatani^*, Yasuko Minaki, Minoru Kumai and Yuichi Ono^*,

KAN Research Institute Inc., KobeMI R&D Center, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, Japan.

Author for correspondence (e-mail: y-ono{at}kan.eisai.co.jp)

Accepted 22 May 2007

The mechanism underlying the determination of neurotransmitter phenotype in the developing mesencephalon, particularly GABAergic versus glutamatergic fate, remains largely unknown. Here, we show in mice that the basic helix-loop-helix transcriptional repressor gene Helt (also known as Megane and Heslike) functions as a selector gene that determines GABAergic over glutamatergic fate in the mesencephalon. Helt was coincidently expressed in all the progenitor domains for mesencephalic GABAergic neurons. In the mesencephalon of Helt-deficient embryos, GABAergic neurons were mostly absent and glutamatergic neurons emerged instead. Conversely, ectopically expressed Helt suppressed glutamatergic formation and induced GABAergic neurogenesis. However, the Helt mutants showed normal progenitor domain formation. In consequence, postmitotic expression of the homeodomain factor Nkx2.2, which was specifically expressed by GABAergic populations in wild-type embryos, was maintained despite the transmitter phenotype conversion from GABAergic to glutamatergic in the Helt mutants, suggesting that Helt is not involved in neuronal identity specification. Furthermore, we identified proneural genes Ngn1 and Ngn2, which were selectively expressed in glutamatergic progenitors in the developing mesencephalon and had the ability to confer the glutamatergic fate, as downstream target genes of Helt. These results suggest that Helt determines GABAergic over glutamatergic fate, at least in part, by repressing Ngn (Neurog) genes and that basic helix-loop-helix transcription factor networks involving Helt and Ngns are commonly used in the mesencephalon for determination of the GABAergic versus glutamatergic transmitter phenotype.

Key words: Helt, Neurogenin, Basic-helix-loop-helix, Transcriptional repressor, GABAergic neurons, Glutamatergic neurons, Mesencephalon, Neuronal identity, Transmitter phenotype determination

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