spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online 1 March 2006
doi: 10.1242/dev.02305

Development 133, 1311-1322 (2006)
Published by The Company of Biologists 2006
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplementary Material
Right arrow All Versions of this Article:
dev.02305v1
133/7/1311    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Elliott, D. A.
Right arrow Articles by Harvey, R. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Elliott, D. A.
Right arrow Articles by Harvey, R. P.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

A tyrosine-rich domain within homeodomain transcription factor Nkx2-5 is an essential element in the early cardiac transcriptional regulatory machinery

David A. Elliott1,*,{dagger}, Mark J. Solloway1,*,{ddagger}, Natalie Wise1, Christine Biben1, Mauro W. Costa1,3, Milena B. Furtado1, Martin Lange1,§, Sally Dunwoodie1,2 and Richard P. Harvey1,2,¶

1 Victor Chang Cardiac Research Institute, Darlinghurst, Sydney 2010, Australia.
2 Faculties of Life Science and Medicine, University of New South Wales, Randwick 2031, Australia.
3 Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, 20941-000, Brazil.

Author for correspondence (e-mail: r.harvey{at}victorchang.unsw.edu.au)

Accepted 31 January 2006

Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development; in humans, mutations in NKX2.5 lead to congenital heart disease (CHD). We have genetically defined a novel conserved tyrosine-rich domain (YRD) within Nkx2-5 that has co-evolved with its homeodomain. Mutation of the YRD did not affect DNA binding and only slightly diminished transcriptional activity of Nkx2-5 in a context-specific manner in vitro. However, the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo. Furthermore, heterozygous mutation of all nine tyrosines to alanine created an allele with a strong dominant-negative-like activity in vivo: ES cell{leftrightarrow}embryo chimaeras bearing the heterozygous mutation died before term with cardiac malformations similar to the more severe anomalies seen in NKX2.5 mutant families. These studies suggest a functional interdependence between the NK2 class homeodomain and YRD in cardiac development and evolution, and establish a new model for analysis of Nkx2-5 function in CHD.

Key words: Heart, Homeodomain, Nkx2-5, Congenital heart disease


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?




© The Company of Biologists Ltd 2006