Tbx1 regulates proliferation and differentiation of multipotent heart progenitors.
BACKGROUND
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.


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.


CONCLUSIONS
The Tbx1 protein marks CPCs, supports their proliferation, and inhibits their differentiation. We propose that Tbx1 is a key regulator of CPC homeostasis as it modulates positively their proliferation and negatively their differentiation.
Chen
Li
L
Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA.
Fulcoli
Filomena Gabriella
FG
Tang
Susan
S
Baldini
Antonio
A
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008938:Mitosis; D039902:Multipotent Stem Cells / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D011485:Protein Binding; D026362:Serum Response Factor / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D026362:Serum Response Factor; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse