Austin J. Cooney, Ph.D.
Associate Professor, Baylor College of Medicine
Department of Molecular and Cellular Biology
Ph.D., National University of Ireland
Postdoctoral, Baylor College of Medicine, Houston
In my laboratory, we are interested in nuclear receptors and their roles in the physiological processes of differentiation and development. Specifically within this superfamily of transcription factors I am interested in elucidating the role of the orphan receptors in these processes. Orphans are an adhoc grouping of receptors that were cloned on the basis of homology to known receptors, however, their functions and their ligands are unknown. The specific cellular differentiation and development processes that I have chosen to study are gametogenesis and embryonic stem cell differentiation. The experimental model system that we employ is the mouse, which permits understanding these processes using transgenic, knock out and ES cell technologies.
We predominantly focus on two orphan receptors one termed Germ Cell Nuclear Factor (GCNF) and the other is Liver receptor homolog-1(Lrh-1). Analysis of GCNF's expression pattern showed high level expression is restricted to the developing gametes in the ovary and testis in the adult, it is also expressed during embryonic development. We are using CreLox knock outs to analyze its role in regulating germ cell cell development.
We have generated a GCNF knockout mouse model. Which is embryonic lethal. The physiological role of GCNF is determined by the genes that it regulates and we have embarked on identifying genes which are GCNF-responsive. We have characterized the GCNF response elements to which it binds, and using this information we have identified a number of genes that have these elements in their promoters, such as the Oct4 gene, which regulates pluriprotence in embryonic stem cells and the germ cell lineage. GCNF plays a major role in turning off the expression of Oct4 in somatic cells after gastrulation, thereby restricting its expression to primordial germ cells. In contrast Lrh-1, which binds to the same response element maintains Oct4 expression in undifferentiated ES cells. We have also generated an Lrh-1 knock out mouse model to study its function in regulating ES cell function.
Fuhrmann, G., Chung, A.C-K., Jackson, K.J., Hummelke, G., Baniahmad, A., Sutter, J., Sylvester, I., Schöler, H.R. and Cooney, A.J. Mouse Germline Restriction of Oct4 Expression by Germ Cell Nuclear Factor. Developmental Cell 1:377-387 (2001). Review: Donovan, P.J. High Oct-ane fuel powers the stem cell. Nature Genetics 29:246-247 (2001).
Lan, Zi-Jian, Chung, A. C-K., Xu, X., DeMayo, F.J. and Cooney, A.J., The embryonic function of germ cell nuclear factor is dependent on the DNA binding domain., J. Biol Chem, 277(52):50660-50667 (2002).
Lan, Zi-Jian, Gu, P., Xu, X. Jackson, K., DeMayo, F.J., O’Malley, B.W. and Cooney, A.J. GCNF-dependent repression of BMP-15 and GDF-9 expression mediates gamete regulation of female fertility. EMBO Journal 22(16):4070-4081, (2003).
Gibbs, R. et al Genome Sequence of the Brown Norway Rat Yields Insight into Mammalian Evolution. Nature 428: 493-521 (2004).
Lan, z.-J., Xu, X. and Cooney, A.J. Differential Oocyte-Specific Expression of Cre Recombinase Activity in GDF-9-iCre, Zp3Cre and Msx2Cre Transgenic Mice. Biol. of Repro. 71: 1469-1474 (2004).
Gu, P., Goodwin, B., Chung, A. C.-K., Xu, X., Wheeler, D., Price, R.R., Galardi, C., Peng, L., Latour, A.M., Koller, B.H. Gossen, J., Kliewer, S.A. and Cooney, A.J. Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development. Molecular and Cellular Biology 25: 3492-3505 (2005).
Gu, P., LeMenuet, D., Chung, A. C.-K., Mancini, M., Wheeler, D. and Cooney, A. J. Orphan nuclear receptor GCNF is required for the repression of pluripotency genes during ES cell differentiation. Mol. Cell. Biol. 25:8507-8519 (2005).
Chung, C-K. A., Xu, X., Neiderreither, K., Cooney, A.J. Orphan Nuclear Receptor GCNF is Required for the Establishment of Forebrain and isthmic organizer. Developmental Biol. 293: 13-24 (2006).
Gu, P., Le Menuet, D., Chung, A. C.-K. and Cooney, A.J. Differential recruitment of MBDs by the orphan receptor GCNF initiates the repression and silencing of Oct4 expression. Mol. Cell. Biol. 26: 9471-9483 (2006).