Tbx1 Regulates Proliferation and Differentiation of Multipotent Heart Progenitors

Abstract

Rationale: TBX1 encodes a T-box transcription factor implicated in DiGeorge syndrome, which affects the development of many organs, including the heart. Loss of Tbx1 results into hypoplasia of heart regions derived from the second heart field, a population of cardiac progenitors cells (CPCs). Thus, we hypothesized that Tbx1 is an important player in the biology of CPCs. Objective: We asked whether Tbx1 is expressed in multipotent CPCs and, if so, what role it may play in them. Methods and Results: We used clonal analysis of Tbx1-expressing cells and loss and gain of function models, in vivo and in vitro, to define the role of Tbx1 in CPCs. We found that Tbx1 is expressed in multipotent heart progenitors that, in clonal assays, can give rise to 3 heart lineages expressing endothelial, smooth muscle and cardiomyocyte markers. In multipotent cells, Tbx1 stimulates proliferation, explaining why Tbx1 ؊/؊ embryos have reduced proliferation in the second heart field. In this population, Tbx1 is expressed while cells are undifferentiated and it disappears with the onset of muscle markers. Loss of Tbx1 results in premature differentiation, whereas gain results in reduced differentiation in vivo. We found that Tbx1 binds serum response factor, a master regulator of muscle differentiation, and negatively regulates its level.

TBX1 regulates epithelial polarity and dynamic basal filopodia in the second heart field

“…The 22q11.2 deletion syndrome candidate gene Tbx1 encodes a key regulator of pharyngeal morphogenesis and SHF development (Chen et al, 2009;Liao et al, 2008). We investigated whether altered epithelial properties are associated with abnormal SHF development in Tbx1 −/− embryos.…”

“…8A-D). TBX1 regulates both proliferation and differentiation in the SHF, and ectopic myocardial differentiation has been observed in the aDPW of Tbx1 −/− embryos (Chen et al, 2009;Liao et al, 2008). We investigated whether altered epithelial properties in the DPW of embryos treated with the aPKCζ activator are associated with ectopic cell differentiation.…”

“…Previous research has focused on the signaling pathways and transcription factors operating in the SHF, including the LIM homeodomain transcription factor Isl1, required for heart tube elongation, and the T-box-containing transcription factor TBX1, required for development of the distal OFT (Cai et al, 2003;Dyer and Kirby, 2009;Xu et al, 2004). TBX1 regulates proliferation and differentiation in the SHF and is the major gene implicated in 22q11.2 deletion (or DiGeorge) syndrome, a primary cause of congenital heart defects affecting the cardiac OFT (Chen et al, 2009;Liao et al, 2008;Pane et al, 2012;Papangeli and Scambler, 2013). However, despite progress in dissecting SHF regulatory networks, basic cellular features of the SHF, including cell polarity, cell shape and cell dynamics, remain to be investigated.…”

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

“…Therefore, we searched for strategies to rescue the T-box 1 (Tbx1) haploinsufficiency phenotype based upon our current understanding of disease pathogenesis. Tbx1 supports cell proliferation and inhibits cell differentiation in the second heart field (SHF), a population of cardiac progenitor cells that migrate and populate the outflow tract and right ventricle (4,5). The gene plays an important, suppressive role in a switch from the progenitor state of SHF cells to the differentiated state as they enter the heart (6).…”

Tbx1 Modulates Endodermal and Mesodermal Differentiation from Mouse Induced Pluripotent Stem Cells

“…progenitor cell population that contributes to the development of most of the heart [30]. Thus, the defective cardiac development in the Tbx1 -/ -iPSCs was possibly due to the reduced mesoderm, cardiac differentiation and/or decreased proliferation of the cardiac progenitor cells.…”