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First published online July 21, 2003
doi: 10.1242/10.1242/dev.00621

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Development 130, 4161-4175 (2003)
Copyright © 2003 The Company of Biologists Limited

Selective degradation of excess Ldb1 by Rnf12/RLIM confers proper Ldb1 expression levels and Xlim-1/Ldb1 stoichiometry in Xenopus organizer functions

Ichiro Hiratani1,2, Naoko Yamamoto1, Toshiaki Mochizuki1,*, Shin-ya Ohmori1,2 and Masanori Taira1,2,{dagger}

1 Department of Biological Sciences, Graduate School of Science, University of Tokyo
2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

{dagger} Author for correspondence (e-mail: m_taira{at}biol.s.u-tokyo.ac.jp).

Accepted 21 May 2003

The Xenopus LIM homeodomain (LIM-HD) protein, Xlim-1, is expressed in the Spemann organizer and cooperates with its positive regulator, Ldb1, to activate organizer gene expression. While this activation is presumably mediated through Xlim-1/Ldb1 tetramer formation, the mechanisms regulating proper Xlim-1/Ldb1 stoichiometry remains largely unknown. We isolated the Xenopus ortholog (XRnf12) of the RING finger protein Rnf12/RLIM and explored its functional interactions with Xlim-1 and Ldb1. Although XRnf12 functions as a E3 ubiquitin ligase for Ldb1 and causes proteasome-dependent degradation of Ldb1, we found that co-expression of a high level of Xlim-1 suppresses Ldb1 degradation by XRnf12. This suppression requires both the LIM domains of Xlim-1 and the LIM interaction domain of Ldb1, suggesting that Ldb1, when bound to Xlim-1, escapes degradation by XRnf12. We further show that a high level of Ldb1 suppresses the organizer activity of Xlim-1/Ldb1, suggesting that excess Ldb1 molecules disturb Xlim-1/Ldb1 stoichiometry. Consistent with this, Ldb1 overexpression in the dorsal marginal zone suppresses expression of several organizer genes including postulated Xlim-1 targets, and importantly, this suppression is rescued by co-expression of XRnf12. These data suggest that XRnf12 confers proper Ldb1 protein levels and Xlim-1/Ldb1 stoichiometry for their functions in the organizer. Together with the similarity in the expression pattern of Ldb1 and XRnf12 throughout early embryogenesis, we propose Rnf12/RLIM as a specific regulator of Ldb1 to ensure its proper interactions with LIM-HD proteins and possibly other Ldb1-interacting proteins in the organizer as well as in other tissues.

Key words: Xenopus, Spemann organizer, Protein-protein interactions, stoichiometry, E3 ubiquitin ligase, Proteasome, RING finger protein, LIM homeodomain protein, XRnf12/RLIM, Ldb1, Xlim-1




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