Hartman Institute for Therapeutic Organ Regeneration

A role for GATA-4/5/6 in the regulation of Nkx2.5 expression with implications for patterning of the precardiac field.

TitleA role for GATA-4/5/6 in the regulation of Nkx2.5 expression with implications for patterning of the precardiac field.
Publication TypeJournal Article
Year of Publication1999
AuthorsJiang Y, Drysdale TA, Evans T
JournalDev Biol
Volume216
Issue1
Pagination57-71
Date Published1999 Dec 01
ISSN0012-1606
KeywordsAnimals, Body Patterning, Cell Differentiation, DNA-Binding Proteins, GATA4 Transcription Factor, GATA5 Transcription Factor, GATA6 Transcription Factor, Gene Expression Regulation, Developmental, Heart, Homeobox Protein Nkx-2.5, Homeodomain Proteins, In Situ Hybridization, Microinjections, RNA, Messenger, Transcription Factors, Tretinoin, Xenopus, Xenopus Proteins
Abstract

Interactions between the key regulatory genes of the cardiogenic pathway, including those from the GATA and Nkx2 transcription factor families, are not well defined. Treating neurula-stage Xenopus embryos with retinoic acid (RA) causes a specific block in cardiomyocyte development that correlates with a progressive reduction in the region of the presumptive heart-forming region expressing Nkx2.5. In contrast, RA does not block expression of the GATA-4/5/6 genes, which are transcribed normally in an overlapping pattern with Nkx2.5 throughout cardiogenesis. Instead, GATA-4/5/6 transcription levels are increased, including an expansion of the expression domain corresponding to lateral plate mesoderm that is part of the early heart field, but that normally is progressively restricted in its ability to contribute to the myocardium. GATA-dependent regulatory sequences of the Nkx2.5 gene that implicate GATA-4/5/6 as upstream positive regulators were described recently. However, our experiments also indicate that GATA factors might normally antagonize transcription of Nkx2.5. To test this hypothesis we generated a dominant negative isoform of GATA-4 (SRG4) capable of inhibiting transcription of GATA-dependent target genes. Ectopic expression of SRG4 results in a transient expansion of the Nkx2.5 transcript pattern, indicating that a normal function of GATA factors is to limit the boundary of the Nkx2.5 expression domain to the most anterior ventral region of the heart field. Regulatory mechanisms altered by excess RA must function normally to limit GATA-4/5/6 expression levels, to define the region of Nkx2.5 expression and regulate myocardial differentiation.

DOI10.1006/dbio.1999.9469
Alternate JournalDev Biol
PubMed ID10588863

Weill Cornell Medicine
Hartman Institute for Therapeutic Organ Regeneration
1300 York Ave, Box 136 New York, NY 10065