Virginia E Papaioannou

Columbia University, New York, New York, United States

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Publications (142)1023.54 Total impact

  • Virginia E. Papaioannou
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    ABSTRACT: Cell lineage is the framework for understanding cellular diversity, stability of differentiation, and its relationship to pluripotency. The special condition of in utero development in mammals has presented challenges to developmental biologists in tracing cell lineages but modern imaging and cell marking techniques have allowed the gradual elucidation of lineage relationships. Early experimental embryology approaches had limited resolution and relied of suboptimal cell markers and considerable disturbance to the embryos. Transgenic technology introduced genetic markers, particularly fluorescent proteins that, combined with sophisticated imaging modalities, greatly increase resolution and allow clonal analysis within lineages. The concept of cell lineage has also undergone evolution as it became possible to trace the lineage of cells based not only on their physical location or attributes but also on their gene expression pattern, thus opening up mechanistic lines of investigation into the determinants of cell lineage.
    No preview · Article · Jan 2016 · Current Topics in Developmental Biology
  • Nataki C. Douglas · Andrew J. Washkowitz · L.A. Naiche · Virginia E. Papaioannou
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    ABSTRACT: The T-box gene family consists of 17 related genes that encode DNA binding proteins that function as transcription factors important in many developmental processes. TBX1 has been identified as a major factor in the DiGeorge deletion syndrome and mutations in other T-box genes result in developmental syndromes (. TBX3, ulnar mammary; TBX4, small patella; TBX5, Holt-Oram; TBX15, Cousin; TBX22, cleft palate with ankyloglossia) or developmental anomalies (. TBX6, spondylocostal dysostosis; TBX19, isolated ACTH deficiency; TBX20, congenital heart disease). Most congenital abnormalities resulting from mutations in T-box genes have effects in heterozygotes with more severe effects in homozygotes, indicating dosage sensitivity. Mouse models are being used to explore the mechanism of action of these and other T-box genes during development and to point the way to recognizing the full range of possible phenotypes. Sophisticated genetic engineering experiments in mice and the study of naturally occurring mutations in humans will continue to reveal the multiple developmental roles of T-box genes.
    No preview · Chapter · Dec 2015
  • Matthew J. Borok · Virginia E. Papaioannou · Lori Sussel
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    ABSTRACT: Gata4 and Gata6 are closely related transcription factors that are essential for the development of a number of embryonic tissues. While they have nearly identical DNA-binding domains and similar patterns of expression, Gata4 and Gata6 null embryos have strikingly different embryonic lethal phenotypes. To determine whether the lack of redundancy is due to differences in protein function or Gata4 and Gata6 expression domains, we generated mice that contained the Gata6 cDNA in place of the Gata4 genomic locus. Gata4(Gata6/Gata6) embryos survived through embryonic day (E)12.5 and successfully underwent ventral folding morphogenesis, demonstrating that Gata6 is able to replace Gata4 function in extraembryonic tissues. Surprisingly, Gata6 is unable to replace Gata4 function in the septum transversum mesenchyme or the epicardium, leading to liver agenesis and lethal heart defects in Gata4(Gata6/Gata6) embryos. These studies suggest that Gata4 has evolved distinct functions in the development of these tissues that cannot be performed by Gata6, even when it is provided in the identical expression domain. Our work has important implications for the respective mechanisms of Gata function during development, as well as the functional evolution of these essential transcription factors.
    No preview · Article · Dec 2015 · Developmental Biology
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    ABSTRACT: Angiogenesis is essential for uterine decidualization, the progesterone-mediated transformation of the uterus allowing embryo implantation and initiation of pregnancy. In the current study, we define the vasculature, expression of Notch proteins and Notch ligands, and Notch activity in both endothelial cells and vascular-associated mural cells of blood vessels in the pre-implantation endometrium and post-implantation decidua of the mouse uterus. We used immunofluorescence to determine the expression of Notch in endothelial cells and mural cells by co-staining for the endothelial cell marker, CD31, the pan-mural cell marker, platelet-derived growth factor receptor beta (PDGFR-β), the pericyte markers, neural/glial antigen 2 (NG2) and desmin, or the smooth muscle cell marker, alpha smooth muscle actin (SMA). A fluorescein isothiocyanate-labeled dextran tracer, was used to identify functional peri-implantation vasculature. CBF:H2B-Venus Notch reporter transgenic mice were used to determine Notch activity. Notch signaling is observed in endothelial cells and pericytes in the peri-implantation uterus. Prior to implantation, Notch1, Notch2 and Notch4 and Notch ligand, Delta-like 4 (Dll4) are expressed in capillary endothelial cells, while Notch3 is expressed in the pericytes. Jagged1 is expressed in both capillary endothelial cells and pericytes. After implantation, Notch1, Notch4 and Dll4 are expressed in endothelial cells of newly formed decidual capillaries. Jagged1 is expressed in endothelial cells of spiral arteries and a subset of decidual pericytes. Notch proteins are not expressed in lymphatic vessels or macrophages in the peri-implantation uterus. We show Notch activity and distinct expression patterns for Notch proteins and ligands, suggesting unique roles for Notch1, Notch4, Dll4, and Jag1 during decidual angiogenesis and early placentation. These data set the stage for loss-of-function and gain-of-function studies that will determine the cell-type specific requirements for Notch proteins in decidual angiogenesis and placentation.
    Full-text · Article · Dec 2015 · Vascular Cell
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    ABSTRACT: The maintenance and control of pluripotency is of great interest in stem cell biology. The dual specificity T-box/basic-helix-loop-helix-zipper transcription factor Mga is expressed in the pluripotent cells of the inner cell mass (ICM) and epiblast of the peri-implantation mouse embryo, but its function has not been investigated previously. Here, we use a loss-of-function allele and RNA knockdown to demonstrate that Mga depletion leads to the death of proliferating pluripotent ICM cells in vivo and in vitro, and the death of embryonic stem cells (ESCs) in vitro. Additionally, quiescent pluripotent cells lacking Mga are lost during embryonic diapause. Expression of Odc1, the rate-limiting enzyme in the conversion of ornithine into putrescine in the synthesis of polyamines, is reduced in Mga mutant cells, and the survival of mutant ICM cells as well as ESCs is rescued in culture by the addition of exogenous putrescine. These results suggest a mechanism whereby Mga influences pluripotent cell survival through regulation of the polyamine pool in pluripotent cells of the embryo, whether they are in a proliferative or quiescent state. © 2015. Published by The Company of Biologists Ltd.
    No preview · Article · Jan 2015 · Development
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    Virginia E Papaioannou
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    ABSTRACT: The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. T-box proteins are characterized by a DNA-binding motif known as the T-domain that binds DNA in a sequence-specific manner. In humans, mutations in many of the genes within the T-box family result in developmental syndromes, and there is increasing evidence to support a role for these factors in certain cancers. In addition, although early studies focused on the role of T-box factors in early embryogenesis, recent studies in mice have uncovered additional roles in unsuspected places, for example in adult stem cell populations. Here, I provide an overview of the key features of T-box transcription factors and highlight their roles and mechanisms of action during various stages of development and in stem/progenitor cell populations.
    Preview · Article · Oct 2014 · Development
  • Daniel Concepcion · Virginia E Papaioannou
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    ABSTRACT: Background: Mutations in the T-box gene Brachyury have well known effects on invagination of the endomesodermal layer during gastrulation, but the gene also plays a role in the determination of left/right axis determination that is less well studied. Previous work has implicated node morphology in this effect. We use the T(Wis) allele of Brachyury to investigate the molecular and morphological effects of the T locus on axis determination in the mouse. Results: Similar to embryos mutant for the T allele, T(Wis) /T(Wis) embryos have a high incidence of ventral and/or reversed heart looping. In addition, heterotaxia between the direction of heart looping and the direction of embryo turning is common. Scanning electron microscopy reveals defects in node morphology including irregularity, smaller size, and a decreased number of cilia, although the cilia appear morphologically normal. Molecular analysis shows a loss of perinodal expression of genes involved in Nodal signaling, namely Cer2, Gdf1, and Nodal itself. There is also loss of Dll1 expression, a key component of the Notch signaling pathway, in the presomitic mesoderm. Conclusions: Morphological abnormalities of the node as well as disruptions of the molecular cascade of left/right axis determination characterize T(Wis) /T(Wis) mutants. Decreased Notch signaling may account for both the morphological defects and the absence of expression of genes in the Nodal signaling pathway.
    No preview · Article · Aug 2014 · Developmental Dynamics
  • Anne Glaser · Ripla Arora · Sandra Hoffmann · Li Li · Norbert Gretz · Virginia E Papaioannou · Gudrun A Rappold
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    ABSTRACT: Background: The short stature homeodomain transcription factors SHOX and SHOX2 play key roles in limb formation. To gain more insight into genes regulated by Shox2 during limb development, we analyzed expression profiles of WT and Shox2-/- mouse embryonic limbs and identified the T-Box transcription factor Tbx4 as a potential downstream target. Tbx4 is known to exert essential functions in skeletal and muscular hindlimb development. In humans, haploinsufficiency of TBX4 causes small patella syndrome, a skeletal dysplasia characterized by anomalies of the knee, pelvis, and foot. Results: Here, we demonstrate an inhibitory regulatory effect of Shox2 on Tbx4 specifically in the forelimbs. We also show that Tbx4 activates Shox2 expression in fore- and hindlimbs, suggesting Shox2 as a feedback modulator of Tbx4. Using EMSA studies, we find that Tbx4/TBX4 is able to bind to distinct T-box binding sites within the mouse and human Shox2/SHOX2 promoter. Conclusions: Our data identifies Tbx4 as a novel transcriptional activator of Shox2 during murine fore- and hindlimb development. Tbx4 is also regulated by Shox2 specifically in the forelimb bud possibly via a feedback mechanism. These data extend our understanding of the role and regulation of Tbx4 and Shox2 in limb development and limb associated diseases.
    No preview · Article · May 2014 · Developmental Dynamics
  • Svetlana Gavrilov · Virginia E. Papaioannou · Donald W. Landry
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    ABSTRACT: This chapter discusses two alternative approaches to yielding genetically unmodified human embryonic stem (ES) cells that do not interfere with the developmental potential of human embryos. One of the approaches is single blastomere biopsy, which is successfully used as a source of material to derive ES cell lines. Human ES cells are created from a single blastomere that is removed from the embryo utilizing a technique originally developed for preimplantation genetic diagnosis (PGD). Another approach uses organismically dead embryos, which involves the derivation of human ES cells from irreversibly arrested, nonviable human embryos that have died during the course of in vitro fertilization (IVF) for reproductive purposes. A retrospective analysis of the morphological progression from ED5 to ED6 in 2,480 embryos that are rejected for clinical use is carried out in order to define morphological criteria that can be used to predict the capacity of discarded, irreversibly arrested, nonviable embryos to give rise to a human ES cell line. Embryos are given a morphological category, commonly used for clinical grading as per standard IVF practice such as single-celled embryo, multicell, morula, and blastocyst. If an embryo has reached the blastocyst stage, it is given an overall grade of good, fair, or poor and is also scored for inner cell mass and trophectoderm quality. The analysis shows that nonviable embryos defined as poor do not improve with extended in vitro culture and yet retain the capacity to yield human ES cell lines despite arrested development.
    No preview · Article · Dec 2013
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    ABSTRACT: Primordial germ cells (PGCs) are the founder cells of the germline. Via gametogenesis and fertilisation this lineage generates a new embryo in the next generation. PGCs are also the cell of origin of multilineage teratocarcinomas. In vitro, mouse PGCs can give rise to embryonic germ (EG) cells - pluripotent stem cells that can contribute to primary chimaeras when introduced into pre-implantation embryos. Thus, PGCs can give rise to pluripotent cells in the course of the developmental cycle, during teratocarcinogenesis and by in vitro culture. However, there is no evidence that PGCs can differentiate directly into somatic cell types. Furthermore, it is generally assumed that PGCs do not contribute to chimaeras following injection into the early mouse embryo. However, these data have never been formally published. Here, we present the primary data from the original PGC-injection experiments performed 40 years ago, alongside results from more recent studies in three separate laboratories. These results have informed and influenced current models of the relationship between pluripotency and the germline cycle. Current technologies allow further experiments to confirm and expand upon these findings and allow definitive conclusions as to the developmental potency of PGCs.
    Full-text · Article · Nov 2013 · Developmental Biology
  • Nataki Celeste Douglas · Ripla Arora · Cayla Yiyu Chen · Mark V Sauer · Virginia E Papaioannou
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    ABSTRACT: Normal development of germ cells is essential for fertility and mammalian reproduction. Although abnormal development of oocytes or follicles may lead to primary ovarian insufficiency (POI), a disorder that causes infertility in 1% of women less than 40 yr of age, the genes and signaling pathways activated in POI are not as yet fully elucidated. Tbx4, a member of the T-box family of transcription factors, is expressed in embryonic germ cells and postnatal oocytes at all stages of folliculogenesis. To investigate the requirement for Tbx4 in the germline, we analyzed germ cell development in the absence of Tbx4. We show that primordial germ cells (PGCs) are reduced in Tbx4 homozygous null (Tbx4(-/-)) embryos at Embryonic Day (E) 10.0. Tbx4(-/-) embryos die by E10.5; to study later time points in vitro a tamoxifen inducible estrogen receptor Cre recombinase was used to delete Tbx4 conditional mutant alleles. In addition, Gdf9cre and Zp3cre, two oocyte-specific Cre recombinases, were used to delete Tbx4 from postnatal primordial and primary follicles, respectively. We show that in vitro differentiation of the gonad into morphologically distinct testes and ovaries occurs normally when Tbx4 is deleted starting at E11.5. In Gdf9cre; Tbx4(fl/-) and Zp3cre; Tbx4(fl/-) adult females, primordial, primary, secondary, and antral follicles form, ovulation occurs, corpus luteum formation is normal, and the mice are fertile without any evidence of diminished ovarian reserve. Although postnatal deletion of Tbx4 in oocytes does not obviously impair fertility, it is possible that the reduction in PGCs observed in Tbx4 homozygous null mutant embryos could affect long-term fertility in adults.
    No preview · Article · Oct 2013 · Biology of Reproduction
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    Svetlana Gavrilov · Richard P Harvey · Virginia E Papaioannou
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    ABSTRACT: Members of the T-box family of transcription factors are important regulators orchestrating the complex regionalization of the developing mammalian heart. Individual mutations in Tbx20 and Tbx3 cause distinct congenital heart abnormalities in the mouse: Tbx20 mutations result in failure of heart looping, developmental arrest and lack of chamber differentiation, while hearts of Tbx3 mutants progress further, loop normally but show atrioventricular convergence and outflow tract defects. The two genes have overlapping areas of expression in the atrioventricular canal and outflow tract of the heart but their potential genetic interaction has not been previously investigated. In this study we produced compound mutants to investigate potential genetic interactions at the earliest stages of heart development. We find that Tbx20; Tbx3 double heterozygous mice are viable and fertile with no apparent abnormalities, while double homozygous mutants are embryonic lethal by midgestation. Double homozygous mutant embryos display abnormal cardiac morphogenesis, lack of heart looping, expression patterns of cardiac genes and time of death that are indistinguishable from Tbx20 homozygous mutants. Prior to death, the double homozygotes show an overall developmental delay similar to Tbx3 homozygous mutants. Thus the effects of Tbx20 are epistatic to Tbx3 in the heart but Tbx3 is epistatic to Tbx20 with respect to developmental delay.
    Full-text · Article · Jul 2013 · PLoS ONE
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    Irfan Saadi · Pragnya Das · Minglian Zhao · Lakshmi Raj · Intan Ruspita · Yan Xia · Virginia E Papaioannou · Marianna Bei
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    ABSTRACT: Bmp4 expression is tightly regulated during embryonic tooth development, with early expression in the dental epithelial placode leading to later expression in the dental mesenchyme. Msx1 is among several transcription factors that are induced by epithelial Bmp4 and that, in turn, are necessary for the induction and maintenance of dental mesenchymal Bmp4 expression. Thus, Msx1(-/-) teeth arrest at early bud stage and show loss of Bmp4 expression in the mesenchyme. Ectopic expression of Bmp4 rescues this bud stage arrest. We have identified Tbx2 expression in the dental mesenchyme at bud stage and show that this can be induced by epithelial Bmp4. We also show that endogenous Tbx2 and Msx1 can physically interact in mouse C3H10T1/2 cells. In order to ascertain a functional relationship between Msx1 and Tbx2 in tooth development, we crossed Tbx2 and Msx1 mutant mice. Our data show that the bud stage tooth arrest in Msx1(-/-) mice is partially rescued in Msx1(-/-);Tbx2(+/-) compound mutants. This rescue is accompanied by formation of the enamel knot (EK) and by restoration of mesenchymal Bmp4 expression. Finally, knockdown of Tbx2 in C3H10T1/2 cells results in an increase in Bmp4 expression. Together, these data identify a novel role for Tbx2 in tooth development and suggest that, following their induction by epithelial Bmp4, Msx1 and Tbx2 in turn antagonistically regulate odontogenic activity that leads to EK formation and to mesenchymal Bmp4 expression at the key bud-to-cap stage transition.
    Full-text · Article · May 2013 · Development
  • Nataki C Douglas · Virginia E Papaioannou
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    ABSTRACT: TBX2 and TBX3, closely related members of the T-box family of transcription factor genes, are expressed in mammary tissue in both humans and mice. Ulnar mammary syndrome (UMS), an autosomal dominant disorder caused by mutations in TBX3, underscores the importance of TBX3 in human breast development, while abnormal mammary gland development in Tbx2 or Tbx3 mutant mice provides models for experimental investigation. In addition to their roles in mammary development, aberrant expression of TBX2 and TBX3 is associated with breast cancer. TBX2 is preferentially amplified in BRCA1/2-associated breast cancers and TBX3 overexpression has been associated with advanced stage disease and estrogen-receptor-positive breast tumors. The regulation of Tbx2 and Tbx3 and the downstream targets of these genes in development and disease are not as yet fully elucidated. However, it is clear that the two genes play unique, context-dependent roles both in mammary gland development and in mammary tumorigenesis.
    No preview · Article · Apr 2013 · Journal of Mammary Gland Biology and Neoplasia
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    ABSTRACT: Danforth's short tail mutant (Sd) mouse, first described in 1930, is a classic spontaneous mutant exhibiting defects of the axial skeleton, hindgut, and urogenital system. We used meiotic mapping in 1,497 segregants to localize the mutation to a 42.8-kb intergenic segment on chromosome 2. Resequencing of this region identified an 8.5-kb early retrotransposon (ETn) insertion within the highly conserved regulatory sequences upstream of Pancreas Specific Transcription Factor, 1a (Ptf1a). This mutation resulted in up to tenfold increased expression of Ptf1a as compared to wild-type embryos at E9.5 but no detectable changes in the expression levels of other neighboring genes. At E9.5, Sd mutants exhibit ectopic Ptf1a expression in embryonic progenitors of every organ that will manifest a developmental defect: the notochord, the hindgut, and the mesonephric ducts. Moreover, at E 8.5, Sd mutant mice exhibit ectopic Ptf1a expression in the lateral plate mesoderm, tail bud mesenchyme, and in the notochord, preceding the onset of visible defects such as notochord degeneration. The Sd heterozygote phenotype was not ameliorated by Ptf1a haploinsufficiency, further suggesting that the developmental defects result from ectopic expression of Ptf1a. These data identify disruption of the spatio-temporal pattern of Ptf1a expression as the unifying mechanism underlying the multiple congenital defects in Danforth's short tail mouse. This striking example of an enhancer mutation resulting in profound developmental defects suggests that disruption of conserved regulatory elements may also contribute to human malformation syndromes.
    Full-text · Article · Feb 2013 · PLoS Genetics
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    ABSTRACT: Early mammalian embryonic development is characterized by the existence of pluripotent or multipotent cell populations that are present for limited periods of time during lineage specification and cellular differentiation. In addition to the pluripotent embryonic stem cell lines that can be derived from the epiblast lineage of the inner cell mass of the blastocyst, stem cell lines have now been derived from the trophectoderm layer, the primitive endoderm, and the postimplantation epiblast, as well as from the primordial germ cells. These stem cell lines generally have the developmental potential and characteristics corresponding to their tissue of origin and the conditions for their derivation reflect the intrinsic genetic programs of lineage specification and differentiation. The extensive investigation of mouse embryo-derived stem cell lines has paved the way for therapeutic applications of stem cells. The derivation of pluripotent stem cells from human embryos as well as the development of induced pluripotent stem cell lines from non-embryo sources brings widespread application of stem cell-based therapies closer to reality.
    No preview · Chapter · Jan 2013
  • Ripla Arora · Chelsea M Del Alcazar · Edward E Morrisey · L A Naiche · Virginia E Papaioannou
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    ABSTRACT: Loss of Tbx4 results in absence of chorio-allantoic fusion and failure of formation of the primary vascular plexus of the allantois leading to embryonic death at E10.5. We reviewed the literature for genes implicated in chorio-allantoic fusion, cavitation and vascular plexus formation, processes affected in Tbx4 mutant allantoises. Using this candidate gene approach, we identified a number of genes downstream of Tbx4 in the allantois including extracellular matrix molecules Vcan, Has2, and Itgα5, transcription factors Snai1 and Twist, and signaling molecules Bmp2, Bmp7, Notch2, Jag1 and Wnt2. In addition, we show that the canonical Wnt signaling pathway contributes to the vessel-forming potential of the allantois. Ex vivo, the Tbx4 mutant phenotype can be rescued using agonists of the Wnt signaling pathway and, in wildtype allantoises, an inhibitor of the canonical Wnt signaling pathway disrupts vascular plexus formation. In vivo, Tbx4 and Wnt2 double heterozygous placentas show decreased vasculature suggesting interactions between Tbx4 and the canonical Wnt signaling pathway in the process of allantois-derived blood vessel formation.
    No preview · Article · Aug 2012 · PLoS ONE
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    Ripla Arora · Ross J Metzger · Virginia E Papaioannou
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    ABSTRACT: Normal development of the respiratory system is essential for survival and is regulated by multiple genes and signaling pathways. Both Tbx4 and Tbx5 are expressed throughout the mesenchyme of the developing lung and trachea; and, although multiple genes are known to be required in the epithelium, only Fgfs have been well studied in the mesenchyme. In this study, we investigated the roles of Tbx4 and Tbx5 in lung and trachea development using conditional mutant alleles and two different Cre recombinase transgenic lines. Loss of Tbx5 leads to a unilateral loss of lung bud specification and absence of tracheal specification in organ culture. Mutants deficient in Tbx4 and Tbx5 show severely reduced lung branching at mid-gestation. Concordant with this defect, the expression of mesenchymal markers Wnt2 and Fgf10, as well as Fgf10 target genes Bmp4 and Spry2, in the epithelium is downregulated. Lung branching undergoes arrest ex vivo when Tbx4 and Tbx5 are both completely lacking. Lung-specific Tbx4 heterozygous;Tbx5 conditional null mice die soon after birth due to respiratory distress. These pups have small lungs and show severe disruptions in tracheal/bronchial cartilage rings. Sox9, a master regulator of cartilage formation, is expressed in the trachea; but mesenchymal cells fail to condense and consequently do not develop cartilage normally at birth. Tbx4;Tbx5 double heterozygous mutants show decreased lung branching and fewer tracheal cartilage rings, suggesting a genetic interaction. Finally, we show that Tbx4 and Tbx5 interact with Fgf10 during the process of lung growth and branching but not during tracheal/bronchial cartilage development.
    Preview · Article · Aug 2012 · PLoS Genetics
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    Ripla Arora · Virginia E Papaioannou
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    ABSTRACT: The allantois is the embryonic precursor of the umbilical cord in mammals and is one of several embryonic regions, including the yolk sac and dorsal aorta, that undergoes vasculogenesis, the de novo formation of blood vessels. Despite its importance in establishing the chorioallantoic placenta and umbilical circulation, the allantois frequently is overlooked in embryologic studies. Nonetheless, recent studies demonstrate that vasculogenesis, vascular remodeling, and angiogenesis are essential allantois functions in the establishment of the chorioallantoic placenta. Here, we review blood vessel formation in the murine allantois, highlighting the expression of genes and involvement of pathways common to vasculogenesis or angiogenesis in other parts of the embryo. We discuss experimental techniques available for manipulation of the allantois that are unavailable for yolk sac or dorsal aorta, and review how this system has been used as a model system to discover new genes and mechanisms involved in vessel formation. Finally, we discuss the potential of the allantois as a model system to provide insights into disease and therapeutics.
    Preview · Article · Jul 2012 · Blood
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    Andrew J Washkowitz · Svetlana Gavrilov · Salma Begum · Virginia E Papaioannou
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    ABSTRACT: The T-box transcription factor Tbx3 plays multiple roles in normal development and disease. In order to function in different tissues and on different target genes, Tbx3 binds transcription factors or other cofactors specific to temporal or spatial locations. Examining the development of the mammary gland, limbs, and heart as well as the biology of stem cells and cancer provides insights into the diverse and common functions that Tbx3 can perform. By either repressing or activating transcription of target genes in a context-dependent manner, Tbx3 is able to modulate differentiation of immature progenitor cells, control the rate of cell proliferation, and mediate cellular signaling pathways. Because the direct regulators of these cellular processes are highly context-dependent, it is essential that Tbx3 has the flexibility to regulate transcription of a large group of targets, but only become a active on a small cohort of them at any given time or place. Moreover, Tbx3 must be responsive to the variety of different upstream factors that are present in different tissues. Only by understanding the network of genes, proteins, and molecules with which Tbx3 interacts can we hope to understand the role that Tbx3 plays in normal development and how its aberrant expression can lead to disease. Because of its myriad functions in disparate developmental and disease contexts, Tbx3 is an ideal candidate for a systems-based approach to genetic function and interaction. WIREs Syst Biol Med 2012. doi: 10.1002/wsbm.1162 For further resources related to this article, please visit the WIREs website.
    Full-text · Article · May 2012 · Wiley Interdisciplinary Reviews Systems Biology and Medicine

Publication Stats

12k Citations
1,023.54 Total Impact Points


  • 1994-2015
    • Columbia University
      • • Department of Genetics and Development
      • • College of Physicians and Surgeons
      New York, New York, United States
    • Boston University
      • Department of Biology
      Boston, Massachusetts, United States
  • 2007-2013
    • CUNY Graduate Center
      New York, New York, United States
  • 2005
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1998
    • Princeton University
      • Department of Molecular Biology
      Princeton, New Jersey, United States
  • 1995
    • Nevada cancer institute
      Las Vegas, Nevada, United States
  • 1989-1995
    • Harvard Medical School
      • Department of Cell Biology
      Boston, Massachusetts, United States
    • Tufts Medical Center
      Boston, Massachusetts, United States
  • 1992
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1985-1989
    • Tufts University
      • School of Dental Medicine
      Бостон, Georgia, United States
    • Brock University
      • Department of Biological Sciences
      St. Catharines, Ontario, Canada