Area: Molecular & Cellular Biology
Drs. Tsai and Tsai have played an essential role in creating a new field on nuclear orphan receptors. Their nomination for this award was based on major contributions to the role of COUP-TFII. They showed that COUP-TFII is overexpressed in metastatic prostate cancer and its expression is an excellent prognostic marker for aggressive prostate cancer.
They further showed that COUP-TFII could break down the barrier inducted by indolent prostate cancer and promote the progression of cancer into an aggressive state. In another study, they found that COUP-TFII controls ~50 percent of the expression of all atrium and ventricle specific genes, which suggests that COUP-TFII is the major regulator determining the specification of atrium vs ventricle during heart development.
Finally, they showed that COUP-TFII directly regulated the expression of both Eya1 and Wt1 in the metanephric mesenchyme. Their findings show that COUP-TFII plays a central role in the specification of metanephric fate and in the maintenance of metanephric mesenchyme proliferation and survival by acting as a crucial regulator of Eya1 and Wt1 expression.
Drs. Tsai and Tsai’s nomination was based on the following publications:
Qin J, Wu SP, Creighton CJ, Dai F, Xie X, Cheng CM, Frolov A, Ayala G, Lin X, Feng XH, Ittmann MM, Tsai SJ, Tsai MJ, Tsai SY. COUP-TFII inhibits TGF-β-induced growth barrier to promote prostate tumorigenesis. Nature. 2013 Jan 10; 493(7431):236-40.
Wu SP, Cheng CM, Lanz RB, Wang T, Respress JL, Ather S, Chen W, Tsai SJ, Wehrens XH, Tsai MJ, Tsai SY. Atrial identity is determined by a COUP-TFII regulatory network Dev Cell. 2013 May 28; 25(4):417-26.
Yu CT1, Tang K, Suh JM, Jiang R, Tsai SY, Tsai MJ. COUP-TFII is essential for metanephric mesenchyme formation and kidney precursor cell survival. Development. 2012 Jul;139(13):2330-9.
Nuclear orphan receptor COUP-TFII and organogenesis
Ming-Jer Tsai, Ph.D. and Sophia Y. Tsai, Ph.D., both received the award for their research in dissecting the in vivo function of nuclear orphan receptors, COUP-TFI and COUP-TFII. COUP-TFs have been shown to play important roles in development. COUP-TFI null mice exhibit defects in axon guidance, in cortical layer formation, in brain regionalization, and axon myelination. These results indicate that COUP-TFI is critical for the function of the central and peripheral nervous system. COUP-TFII null mice display defects in angiogenesis and heart development and die before E 10.0. Tissue specific knock out of COUP-TFII in the stomach shows posterior transformation and aberrant muscle differentiation. Both phenotypes implicate COUP-TFII as a mediator of the hedgehog signaling pathway. In addition, haploid insufficiency is shown in COUP-TFII heterozygous mutants. The expression patterns and the phenotypes exhibited by the COUP-TFII mutants suggest that COUP-TFII is essential for organogenesis in tissues requiring mesenchymal-epithelial interactions. Taken together, the above findings indicate that COUP-TFI and COUP-TFII serve vital functions during development and raise the possibility of future ligand based therapy for disease treatment.
Dr. Tsai and Tsai’s research was based on the following publications:
Pereira FA, Qiu Y, Zhou G, Tsai MJ, Tsai SY. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 1999 Apr 15;13(8):1037-49.
Zhou C, Qiu Y, Pereira FA, Crair MC, Tsai SY, Tsai MJ. The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons. Neuron. 1999 Dec;24(4):847-59.
Huang HP, Liu M, El-Hodiri HM, Chu K, Jamrich M, Tsai MJ. Regulation of the pancreatic islet-specific gene BETA2 (neuroD) by neurogenin 3. Mol Cell Biol. 2000 May;20(9):3292-307.
Zhou C, Tsai SY, Tsai MJ. COUP-TFI: an intrinsic factor for early regionalization of the neocortex.Genes Dev. 2001 Aug 15;15(16):2054-9.