Defining New Roles for TBX3 in Stem Cells

• Main Author: Esmailpour, Taraneh
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01.01.2012
• Subjects: Cellular biology; Developmental biology; Oncology
• ISBN: 1267110953; 9781267110954

The T-box transcription factor TBX3 is critical for early embryonic development and for the normal development of the mammary glands. Homozygous mutations in mice are embryonic lethal while heterozygous mutations result in perturbed mammary gland development. In humans, mutations that result in the haploinsufficiency of TBX3 cause Ulnar Mammary Syndrome characterized by mammary gland hypoplasia. TBX3 is over-expressed in breast cancer cell lines and cancer tissue. Overexpression of Tbx3 contributes to breast cancer cell migration. Although studies have implied that aberrant TBX3 expression contributes to cancer progression, the causal role of TBX3 in breast cancer has not been established. Here, we created doxycycline inducible double transgenic mice to test whether TBX3 over-expression induces tumor formation within the mammary gland. Our results show that the over-expression of TBX3, alone, is not sufficient to induce tumor formation, but accelerated mammary gland development through inhibition of the NF-κB pathway and stimulation of mammary stem-like cell proliferation. In mice, Tbx3 plays an important role in the maintenance of mouse ESC self-renewal and the differentiation into extra-embryonic endoderm (ExEn). Since mouse and human ESCs are known to represent distinct pluripotent states, it is important to address the role of TBX3 in regulating human ESC self-renewal and differentiation. Using over-expression and knockdown strategies, we have defined roles for TBX3 in regulating human ESC proliferation and differentiation. Unlike in mouse ESCs, neither TBX3 over-expression nor knockdown attenuated self-renewal to induce differentiation of human ESCs. Instead, TBX3 over-expression was found to promote stem cell proliferation possibly by repressing the expression of both NFκBIB and p14ARF, known cell cycle regulators. During differentiation, TBX3 knockdown resulted in decreased neural rosette formation and in decreased expression of neuroectoderm markers (PAX6, LHX2, FOXG1, RAX). Taken together, our data suggests a role for TBX3 in human ESC proliferation and reveals an unrecognized novel role of TBX3 in promoting neuroectoderm lineage commitment during differentiation.