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Congenital Heart Disease Reminiscent of Partial Trisomy 2P Syndrome in Mice Transgenic for the Transcription Factor Lbh Karoline J

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Congenital Heart Disease Reminiscent of Partial Trisomy 2P Syndrome in Mice Transgenic for the Transcription Factor Lbh Karoline J Corrigendum 4015 Congenital heart disease reminiscent of partial trisomy 2p syndrome in mice transgenic for the transcription factor Lbh Karoline J. Briegel, H. Scott Baldwin, Jonathan A. Epstein and Alexandra L. Joyner Development 132, 3305-3316. An error in Fig. 7J of the article was not corrected before going to press. Two of the plus signs were mistakenly written as minuses. The correct figure is printed below. The authors apologise to readers for this mistake. J NIH3T3 100 ANF-hGH 90 80 70 60 50 40 30 fold transactivation 20 10 * 0 Lbh + + +++ + + Nkx2.5 + + + + + + Tbx5 + + + + + + Gata4 + + + + + + Development Research article Development and disease 3305 Congenital heart disease reminiscent of partial trisomy 2p syndrome in mice transgenic for the transcription factor Lbh Karoline J. Briegel1,*,†, H. Scott Baldwin2, Jonathan A. Epstein3 and Alexandra L. Joyner1 1Howard Hughes Medical Institute and Developmental Genetics Program, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY 10016, USA 2Departments of Pediatrics and Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA 3Cardiovascular Division, University of Pennsylvania, Philadelphia, PA 19104, USA *Present address: Department of Biochemistry and Molecular Biology, University of Miami School of Medicine, Miami, FL 33136, USA †Author for correspondence (e-mail: [email protected]) Accepted 3 May 2005 Development 132, 3305-3316 Published by The Company of Biologists 2005 doi:10.1242/dev.01887 Summary Partial trisomy 2p syndrome includes a spectrum of abnormalities in ventricular cardiomyocyte growth. congenital heart disease (CHD) that is characterized by Furthermore, we demonstrate that overexpression of Lbh complex malformations of the outflow and inflow tracts, in cultured mammalian cells represses the synergistic defects in cardiac septation, heart position, as well as activity of key cardiac transcription factors, Nkx2.5 and abnormal ventricular development. Lbh (limb-bud and Tbx5, leading to reduced activation of the common target heart) is a novel, highly conserved putative transcriptional gene, Anf (Nppa). Strikingly, reduced levels of Anf regulatory protein, which displays a unique spatiotemporal expression were also observed in embryonic day 9.5 Carp- gene expression pattern during early mouse heart Lbh transgenic mice. Thus, repression of Nkx2.5 and Tbx5- development. Here we show that human LBH maps to mediated gene expression by deregulated Lbh may account chromosome 2p23, a genomic region related to CHD in in part for the cardiac anomalies observed in these mice. partial trisomy 2p syndrome. Remarkably, transgenic Our findings implicate LBH as a candidate gene for CHD overexpression of Lbh in mice throughout the embryonic associated with partial trisomy 2p syndrome and suggest myocardium from a cardiomyocyte-specific promoter of an important role of Lbh in transcriptional control during Development the cardiac ankyrin repeat protein gene (Carp/Ankrd1) normal cardiogenesis. models CHD reported in humans with partial trisomy 2p syndrome. The malformations in Carp-Lbh transgenic mice reflect impaired pulmonary outflow tract valvulogenesis, Key words: Lbh (Limb-bud and heart), Gene regulation, Heart cardiac septation, inflow tract morphogenesis, as well as development, Mouse, Congenital heart disease, Nkx2.5, Tbx5 Introduction foramen ovale (PFO), inflow tract (IFT) anomalies, including Congenital heart disease (CHD) is the most prominent anomalous pulmonary return, as well as abnormally developed developmental anomaly in humans with a prevalence of over ventricles. In addition, dextrocardia and dextro-transposition of 1% of live births (Hoffman and Kaplan, 2002). Yet, the the great arteries (D-TGA) are observed either in isolation or molecular mechanisms leading to CHD are poorly understood. in association with visceral heterotaxy (Francke and Jones, CHD is part of partial trisomy 2p syndrome, a rare autosomal 1976; Lurie et al., 1995; Therkelsen et al., 1973). Of the disorder that is characterized by the triplication of distal approximately 60 partial trisomy 2p cases published so far, regions of the short arm of chromosome 2 arising from over 73% encompass duplications of chromosomal band 2p23 imbalanced translocations of these chromosomal segments to (Lurie et al., 1995; Taylor Clelland et al., 2000). Interestingly, various other chromosomes (Francke and Jones, 1976). Other CHD, as well as postaxial limb defects associated with this typical phenotypes of this syndrome are mental and growth syndrome have been linked to this particular genomic segment retardation, neural tube defects, characteristic craniofacial, (Hahm et al., 1999; Lurie et al., 1995). This suggests that one skeletal and genital anomalies, as well as postaxial limb defects or several genes on chromosome 2p23 are responsible for (Cassidy et al., 1977; Francke and Jones, 1976; Hahm et al., patterning of the heart and the extremities. 1999; Lurie et al., 1995). Syndromic CHD involves outflow We have previously identified a novel mouse protein, tract (OFT) defects, including pulmonary stenosis (PS) and encoded by the Lbh (Limb-bud and heart) gene (Briegel and pulmonary atresia (PA), patent ductus arteriosus (PDA), double Joyner, 2001). Lbh is a member of a highly conserved family outlet right ventricle (DORV), and the cyanotic lesion of small acidic proteins of ~12 kDa in vertebrates that do not Tetralogy of Fallot (TOF) (Cassidy et al., 1977; Neu et al., exhibit any known structural motifs. A Xenopus orthologue of 1979; Therkelsen et al., 1973). Some individuals also display Lbh, termed XlCl2, was originally cloned as a maternal RNA ventricular and atrial septal defects (VSD and ASD), a patent of unknown function that becomes activated in fertilized 3306 Development 132 (14) Research article oocytes by polyadenylation (Paris et al., 1988; Paris and subvalvular obstruction of the pulmonary infundibulum with Philippe, 1990). Lbh proteins share a glutamate-rich putative excessive valve tissue, as well as DORV, D-TGA and TOF. In transcriptional activation domain at the carboxyl terminus that addition, characteristic defects in IFT morphogenesis, cardiac is preceded by a putative nuclear localization signal, but do not septation, heart position and in ventricular development were have any apparent DNA-binding domain (Briegel and Joyner, observed. Finally, we show that Lbh expressed in tissue culture 2001). In keeping with the protein structure, Lbh localizes to cells inhibits Nkx2.5- and Tbx5-mediated activation of cardiac the nucleus and can activate transcription in a reporter assay in target genes and that Anf (Nppa – Mouse Genome Informatics), mammalian tissue culture cells (Briegel and Joyner, 2001). a common target gene, is downregulated in Carp-Lbh Thus, Lbh could act as a tissue-specific transcription cofactor. transgenic mice. Taken together, our studies provide strong During mouse embryogenesis, the dynamic spatiotemporal evidence that LBH is a candidate gene for CHD associated with expression pattern of Lbh reflects the onset of formation and partial trisomy 2p syndrome and that Lbh deregulation patterning events in the limb buds and in the heart (Briegel and interferes with normal cardiac development, in part through the Joyner, 2001). Lbh expression is also detected in primitive gut attenuation of Nkx2.5 and Tbx5 transcription factor function. endoderm, branchial arches, ventral tail ectoderm, urogenital ridge, otic vesicles, oral epithelium and in neural crest-derived sensory neurons (Briegel and Joyner, 2001). At the initial Materials and methods stages of limb outgrowth, Lbh is expressed in ventral limb Radiation hybrid mapping ectoderm and the apical ectodermal ridge (AER). These limb Primers for mouse Lbh were STS-F (5′-GCAAGACAACTGTGAA- ectodermal compartments provide the cues for both ventral GAGGCAAC-3′) and STS-B14 (5′-GTGATTTTCAGGTGCAAA- limb specification and proximodistal limb outgrowth (Chen ACGG-3′), and for human LBH hSTS-A (5′-GACATTTTCAGAA- and Johnson, 1999; Tickle, 1999). In the heart, Lbh expression CAATTC-3′) and hSTS-B (5′-ATAAAGAGCAGTAGAGT-CCC-3′). initiates in the crescent-shaped precardiac mesoderm as early The primers were used against the mouse and human radiation hybrid as expression of the homeodomain transcription factor Nkx2.5 panels from Research Genetics. The data were incorporated into the (Briegel and Joyner, 2001; Lints et al., 1993). Notably, the Jackson Laboratory mouse (MGM) and Stanford University human cardiac crescent expresses Lbh in an anterior-to-posterior radiation hybrid maps and compared against physical linkage and gradient with highest levels of expression in anterior pro- genome sequence data of the OMIM and NCBI databases. cardiomyocytes (Briegel and Joyner, 2001). At the completion Generation of Carp-Lbh transgenic mice of cardiac looping, Lbh expression is highest in the right A HindIII-BamHI fragment comprising an amino-terminally Flag- ventricle (RV), the atrio-ventricular canal (AVC) and the sinus tagged Lbh coding region from pcDNA/NFlag-Lbh (Briegel and venosus (SV), but is excluded from atrial myocardium and Joyner, 2001) was blunt-end ligated into the SnaBI site of the endocardial structures. Once chamber formation has occurred, transgenic vector PEVII (Kimmel et al., 2000). A 2.5 kb Carp cardiac- the right-sided Lbh expression in ventricular myocardium is specific promoter contained on a BamHI-XhoI fragment (Kuo et al., Development lost
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