QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online 15 June 2005
doi: 10.1242/dev.01887

This Article Figures Only Full Text Full Text (PDF) A corrigendum has been published All Versions of this Article: dev.01887v1 132/14/3305    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend 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 Briegel, K. J. Articles by Joyner, A. L. Search for Related Content PubMed PubMed Citation Articles by Briegel, K. J. Articles by Joyner, A. L. Social Bookmarking                         What's this?

Congenital heart disease reminiscent of partial trisomy 2p syndrome in mice transgenic for the transcription factor Lbh

Karoline J. Briegel^1,*,, H. Scott Baldwin², Jonathan A. Epstein³ and Alexandra L. Joyner¹

¹ Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA
² Departments of Pediatrics and Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
³ Cardiovascular Division, University of Pennsylvania, Philadelphia, PA 19104, USA

Author for correspondence (e-mail: kbriegel{at}med.miami.edu)

Accepted 3 May 2005

Partial trisomy 2p syndrome includes a spectrum of congenital heart disease (CHD) that is characterized by complex malformations of the outflow and inflow tracts, defects in cardiac septation, heart position, as well as abnormal ventricular development. Lbh (limb-bud and heart) is a novel, highly conserved putative transcriptional regulatory protein, which displays a unique spatiotemporal gene expression pattern during early mouse heart development. Here we show that human LBH maps to chromosome 2p23, a genomic region related to CHD in partial trisomy 2p syndrome. Remarkably, transgenic overexpression of Lbh in mice throughout the embryonic myocardium from a cardiomyocyte-specific promoter of the cardiac ankyrin repeat protein gene (Carp/Ankrd1) models CHD reported in humans with partial trisomy 2p syndrome. The malformations in Carp-Lbh transgenic mice reflect impaired pulmonary outflow tract valvulogenesis, cardiac septation, inflow tract morphogenesis, as well as abnormalities in ventricular cardiomyocyte growth. Furthermore, we demonstrate that overexpression of Lbh in cultured mammalian cells represses the synergistic activity of key cardiac transcription factors, Nkx2.5 and Tbx5, leading to reduced activation of the common target gene, Anf (Nppa). Strikingly, reduced levels of Anf expression were also observed in embryonic day 9.5 Carp-Lbh transgenic mice. Thus, repression of Nkx2.5 and Tbx5-mediated gene expression by deregulated Lbh may account in part for the cardiac anomalies observed in these mice. Our findings implicate LBH as a candidate gene for CHD associated with partial trisomy 2p syndrome and suggest an important role of Lbh in transcriptional control during normal cardiogenesis.

Key words: Lbh (Limb-bud and heart), Gene regulation, Heart development, Mouse, Congenital heart disease, Nkx2.5, Tbx5

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

This article has been cited by other articles:

				W. M.H. Hoogaars, A. Engel, J. F. Brons, A. O. Verkerk, F. J. de Lange, L.Y. E. Wong, M. L. Bakker, D. E. Clout, V. Wakker, P. Barnett, et al. Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria Genes & Dev., May 1, 2007; 21(9): 1098 - 1112. [Abstract] [Full Text] [PDF]