Identification and localization of TBX5 transcription factor during human cardiac morphogenesis

Mutations in the TBX5 transcription factor gene cause human cardiac malformation in Holt-Oram syndrome. To identify and localize TBX5 during cardiac morphogenesis, we performed immunohistochemical studies of TBX5 protein cardiac expression during human embryogenesis. Specific antibody to human TBX5 was generated in rabbits with a TBX5 synthetic peptide and affinity purification of antiserum. Anti-TBX5 was used in immunohistochemical analyses of human cardiac tissue. In embryonic and adult heart, TBX5 is expressed throughout the epicardium and in cardiomyocyte nuclei in myocardiurn of all four cardiac chambers. Endocardial expression of TBX5 is only present in left ventricle. Asymmetric left-sided transmyocardial gradients of TBX5 protein expression were observed in embryonic but not adult hearts. Human cardiac expression of TBX5 protein correlates with the cardiac manifestations of Holt-Oram syndrome. TBX5 transmyocardial protein gradients may contribute to normal patreining of the human heart during embryogenesis. (C) 2000 Wiley-Liss, Inc

TBX5 transcription factor regulates cell proliferation during cardiogenesis

Mutations in human TBX5, a member of the T-box transcription factor gene family, cause congenital cardiac septation, defects and isomerism in autosomal dominant Holt-Oram syndrome. To determine the cellular function of TBX5 in cardiogenesis, we overexpressed wild-type and mutant human TBX5 isoforms in vitro and in vivo. TBX5 inhibited cell proliferation of D17 canine osteosarcoma cells and MEQC quail cardiomyocyte-like cells in vitro. Mutagenesis of the 5′ end of the T-box but not the 3′ end of the T-box abolished this effect. Overexpression of TBX5 in embryonic chick hearts showed that TBX5 inhibits myocardial growth and trabeculation. TBX5 effects in vivo were abolished by Gly80Arg missense mutation of the 5′ end of the T-box. PCNA analysis in transgenic chick hearts revealed that TBX5 overexpression does suppress embryonic cardiomyocyte proliferation in vivo. Inhibitory effects of TBX5 on cardiomyocyte proliferation include a noncell autonomous process in vitro and in vivo. TBX5 inhibited proliferation of both nontransgenic cells cocultured with transgenic cells in vitro and nontransgenic cardiomyocytes in transgenic chick hearts with mosaic expression of TBX5 in vivo. Immunohistochemical studies of human embryonic tissues, including hearts, also demonstrated that TBX5 expression is inversely related to cellular proliferation. We propose that TBX5 can act as a cellular arrest signal during vertebrate cardiogenesis and thereby participate in modulation of cardiac growth and development. © 2001 Academic Press

TBX5 regulates cardiac cell behavior during cardiogenesis

Mutations in human TBX5 cause congenital structural abnormalities of the heart and limb in autosomal dominant Holt–Oram syndrome.1–3 Holt–Oram syndrome presents as congenital heart disease in the setting of preaxial radial ray limb deformity. Our previous analyses have shown that TBX5 haploinsufficiency causes human atrial and ventricular defects as well as abnormalities of my- ocardial and trabecular structure that reflect cardiac isomerism.2,4..

A role for Tbx5 in proepicardial cell migration during cardiogenesis

Transcriptional regulatory cascades during epicardial and coronary vascular development from proepicardial progenitor cells remain to be defined. We have used immunohistochemistry of human embryonic tissues to demonstrate that the TBX5 transcription factor is expressed not only in the myocardium, but also throughout the embryonic epicardium and coronary vasculature. TBX5 is not expressed in other human fetal vascular beds. Furthermore, immunohistochemical analyses of human embryonic tissues reveals that unlike their epicardial counterparts, delaminating epicardial-derived cells do not express TBX5 as they migrate through the subepicardium before undergoing epithelial-mesenchymal transformation required for coronary vasculogenesis. In the chick, Tbx5 is expressed in the embryonic proepicardial organ (PEO), which is composed of the epicardial and coronary vascular progenitor cells. Retrovirus-mediated overexpression of human TBX5 inhibits cell incorporation of infected proepicardial cells into the nascent chick epicardium and coronary vasculature. TBX5 overexpression as well as antisense-mediated knockdown of chick Tbx5 produce a cell-autonomous defect in the PEO that prevents proepicardial cell migration. Thus, both increasing and decreasing Tbx5 dosage impairs development of the proepicardium. Culture of explanted PEOs demonstrates that untreated chick proepicardial cells downregulate Tbx5 expression during cell migration. Therefore, we propose that Tbx5 participates in regulation of proepicardial cell migration, a critical event in the establishment of the epicardium and coronary vasculature. © 2004 American Physiological Societ

Facets of Impulsivity in the Relationship Between Antisocial Personality and Abstinence

Most individuals who enter drug treatment programs are unable to maintain long-term abstinence. This problem is especially relevant for those presenting with Antisocial Personality Disorder (ASPD). In examining potential mechanisms underlying the relationship between ASPD and abstinence, one factor that may be especially useful is the personality variable of impulsivity. Thus, the current study examined ASPD status in relation to longest abstinence attempt among 117 substance use treatment-seeking individuals, considering the mediating role of five facets of impulsivity: urgency, perseverance, premeditation, control, and delay discounting. Results indicated that individuals with ASPD evidenced shorter previous abstinence attempts and lower levels of perseverance and control than those without ASPD. Further, lower levels of control were associated with shorter abstinence attempts. Finally, control mediated the relationship between ASPD and longest quit attempt. These results suggest the potential value of multiple facets of impulsivity in efforts to understand relapse and subsequent treatment development efforts