Tbx6 is a determinant of cardiac and neural cell fate decisions in multipotent P19CL6 cells.
Multipotent P19CL6 cells differentiate into cardiac myocytes or neural lineages when stimulated with dimethyl sulfoxide (DMSO) or retinoic acid (RA), respectively. Expression of the transcription factor Tbx6 was found to increase during cardiac myocyte differentiation and to decrease during neural differentiation. Overexpression of Tbx6 was not sufficient to drive P19CL6 cells to a cardiac myocyte fate or to accelerate DMSO-induced differentiation. In contrast, knockdown of Tbx6 dramatically inhibited DMSO-induced differentiation of P19CL6 cells to cardiac myocytes, as evidenced by the loss of striated muscle-specific markers and spontaneous beating. Tbx6 knockdown was also accompanied by almost complete loss of Nkx2.5, a transcription factor involved in the specification of the cardiac myocyte lineage, indicating that Nkx2.5 is downstream of Tbx6. In distinction to its positive role in cardiac myocyte differentiation, Tbx6 knockdown augmented RA-induced differentiation of P19CL6 cells to both neurons and glia, and accelerated the rate of neurite formation. Conversely, Tbx6 overexpression attenuated differentiation to neural lineages. Thus, in the P19CL6 model, Tbx6 is required for cardiac myocyte differentiation and represses neural differentiation. We propose a model in which Tbx6 is a part of a molecular switch that modulates divergent differentiation programs within a single progenitor cell.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Svetlana
S
Gavrilov
Thomas G
TG
Nührenberg
Anthony W
AW
Ashton
Chang-Fu
CF
Peng
Jennifer C
JC
Moore
Klitos
K
Konstantinidis
Christine L
CL
Mummery
Richard N
RN
Kitsis
D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019070:Cell Lineage; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology*; D009474:Neurons / Q000166:cytology*; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D034741:RNA, Small Interfering; D020825:T-Box Domain Proteins; C102932:Tbx6 protein, mouse; D014157:Transcription Factors; D014212:Tretinoin; D004121:Dimethyl Sulfoxide