1. Developmental Biology Programme, EMBL, Meyerhofstrasse 1, 69012 Heidelberg, Germany

Correspondence to: Joachim Wittbrodt Correspondence and requests for materials should be addressed to J.W. (Email: Jochen.Wittbrodt@EMBL.de).

The geminin sequence has been submitted to the EMBL database (accession number AJ608707); whole-mount expression data have been submitted to MEPD (Ol_emx1, Ol_geminin, Ol_rx2, Ol_six3, Ol_vax1; http://www.embl-heidelberg.de/mepd/).

Abstract

Organogenesis in vertebrates requires the tight control of cell proliferation and differentiation. The homeobox-containing transcription factor Six3 plays a pivotal role^{1, 2} in the proliferation of retinal precursor cells. In a yeast two-hybrid screen, we identified the DNA replication-inhibitor geminin as a partner of Six3. Geminin inhibits cell-cycle progression³ by sequestering Cdt1 (refs 4, 5), the key component for the assembly of the pre-replication complex⁶. Here, we show that Six3 efficiently competes with Cdt1 directly to bind to geminin, which reveals how Six3 can promote cell proliferation without transcription. In common with Six3 inactivation^{2, 7}, overexpression of the geminin gene (Gem; also known as Gmn) in medaka (Oryzias latipes) induces specific forebrain and eye defects that are rescued by Six3. Conversely, loss of Gem (in common with gain of Six3 (ref. 1)) promotes retinal precursor-cell proliferation and results in expanded optic vesicles, markedly potentiating Six3 gain-of-function phenotypes. Our data indicate that the transcription factor Six3 and the replication-initiation inhibitor geminin act antagonistically to control the balance between proliferation and differentiation during early vertebrate eye development.

1. Developmental Biology Programme, EMBL, Meyerhofstrasse 1, 69012 Heidelberg, Germany

Correspondence to: Joachim Wittbrodt Correspondence and requests for materials should be addressed to J.W. (Email: Jochen.Wittbrodt@EMBL.de).

The geminin sequence has been submitted to the EMBL database (accession number AJ608707); whole-mount expression data have been submitted to MEPD (Ol_emx1, Ol_geminin, Ol_rx2, Ol_six3, Ol_vax1; http://www.embl-heidelberg.de/mepd/).

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