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

Development
David A ElliottRichard P Harvey

Abstract

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<-->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.

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Citations

Dec 18, 2007·Nature Genetics·Ramesh S YadavaMani S Mahadevan
May 14, 2010·Future Cardiology·Antonella CecchettoLuciano Daliento
Aug 7, 2007·Biochemical and Biophysical Research Communications·Hoe Suk KimTakayuki Morisaki
Jan 16, 2007·Seminars in Cell & Developmental Biology·Brad Davidson
Mar 7, 2015·Scientific Reports·Ossama K Abou HassanGeorges M Nemer
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Jun 24, 2008·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Sandra NavetLaure Bonnaud
Aug 26, 2015·ELife·Megan Rowton, Ivan P Moskowitz
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Nov 25, 2011·Acta Biochimica Et Biophysica Sinica·Shuna SunHouyan Song
May 6, 2020·Human Mutation·Jorge E KolomenskiLiliana Dain
Dec 31, 2015·World Journal of Gastroenterology : WJG·Behzad YeganehSaeid Ghavami
Mar 20, 2019·Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution·Neal I CallaghanAntonio V Sykes

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