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First published online 25 June 2008
doi: 10.1242/dev.019794

This Article Figures Only Full Text Full Text (PDF) Supplementary Material All Versions of this Article: dev.019794v1 135/15/2649    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 Tian, J. Articles by Sampath, K. Search for Related Content PubMed PubMed Citation Articles by Tian, J. Articles by Sampath, K. Social Bookmarking                         What's this?

The pro-domain of the zebrafish Nodal-related protein Cyclops regulates its signaling activities

¹ Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604.
² Institute of Medical Biology, Immunos, 8A Biomedical Grove, Singapore 138648.
³ Department of Biological Sciences, 14 Science Drive 4, National University of Singapore, Singapore 117543.
⁴ School of Biological Sciences, Nanyang Technological University, 30 Nanyang Drive, Singapore 637551.

^* Author for correspondence (e-mail: karuna{at}tll.org.sg)

Accepted 6 June 2008

Nodal proteins are secreted signaling factors of the transforming growth factor β (TGFβ) family with essential roles in embryonic development in vertebrates. Mutations affecting the Nodal factors have severe consequences in mammals and fish. Furthermore, increased Nodal levels have been associated with melanoma tumor progression. Like other TGFβ-related proteins, Nodal factors consist of a pro-domain and a mature domain. The pro-domain of mouse Nodal protein stabilizes its precursor. However, the mechanisms by which the pro-domains exert their activities are unknown. Here, we characterize the zebrafish Nodal-related factor Cyclops (Cyc) and find unexpected functions for the pro-domain in regulating Cyc activity. We identified a lysosome-targeting region in the Cyc pro-domain that destabilizes the precursor and restricts Cyc activity, revealing the molecular basis for the short-range signaling activities of Cyc. We show that both the pro- and mature-domains of Cyc regulate its stability. We also characterize a mutation in the pro-domain of human NODAL (hNODAL) that underlies congenital heterotaxia. Heterologous expression of mutant hNODAL increases expression of Nodal-response genes. Our studies reveal unexpected roles for the pro-domain of the Nodal factors and provide a possible mechanism for familial heterotaxia.

Key words: Left-right asymmetry, Nodal signaling, Squint, Mature domain, Pro-domain, Zebrafish, Cyclops

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