Diverse functional networks of Tbx3 in development and disease

Abstract

The T-box transcription factor Tbx3 plays multiple roles in normal development and disease. In order to function in different tissues and on different target genes, Tbx3 binds transcription factors or other cofactors specific to temporal or spatial locations. Examining the development of the mammary gland, limbs, and heart as well as the biology of stem cells and cancer provides insights into the diverse and common functions that Tbx3 can perform. By either repressing or activating transcription of target genes in a context-dependent manner, Tbx3 is able to modulate differentiation of immature progenitor cells, control the rate of cell proliferation, and mediate cellular signaling pathways. Because the direct regulators of these cellular processes are highly context-dependent, it is essential that Tbx3 has the flexibility to regulate transcription of a large group of targets, but only become a active on a small cohort of them at any given time or place. Moreover, Tbx3 must be responsive to the variety of different upstream factors that are present in different tissues. Only by understanding the network of genes, proteins, and molecules with which Tbx3 interacts can we hope to understand the role that Tbx3 plays in normal development and how its aberrant expression can lead to disease. Because of its myriad functions in disparate developmental and disease contexts, Tbx3 is an ideal candidate for a systems-based approach to genetic function and interaction.

Figure 1

Expression of Tbx3 (blue) in developing organ systems at different stages. (A) In mammary gland, Tbx3 is first expressed at E10.5 in the mesenchymal milk line and then appears as one of the earliest markers of the epithelial thickenings known as the mammary placodes. It continues to be expressed in the epithelium as the placode expands into the mammary bud and eventually forms the branching ductal system. Near term (E18.5), mesenchyme surrounding the nipple expresses Tbx3. (B) Tbx3 is first expressed in the posterior margin of the early limb buds and then in the posterior and anterior margins of both fore- and hindlimbs by E10.5. It is also expressed in the AER, continuously at first and then limited to the tips of the digits by E12.5. (C) Tbx3 is expressed in the AVC, SAN, OFT and atrioventricular bundle (AVB) starting around E10.5. It fully delineates the cardiac conduction system at E14.5 with expression in the SAN, AVN, AVB, and the bundle branches (BB).

Figure 2

Diagram of known regulatory pathways and downstream targets of Tbx3 in the development of heart, mammary gland and limbs, as well as in embryonic and iPS stem cells. The variety of factors involved illustrates the context-dependent nature of Tbx3 interactions.

Figure 3

The Tbx3 interactome in cancer. Known and hypothetical molecular interactions between Tbx3 and components of several signaling pathways important in oncogenesis are drawn from a variety of contexts.