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A Hox-Eya-Pax Complex Regulates Early Kidney Developmental Gene Expression ^,

Ke-Qin Gong,^1, Alisha R. Yallowitz,^2, Hanshi Sun,¹ Gregory R. Dressler,³ and Deneen M. Wellik^1,2*

Division of Molecular Medicine and Genetics, Department of Internal Medicine,¹ Department of Cell and Developmental Biology,² Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200³

Received 18 March 2007/ Returned for modification 31 May 2007/ Accepted 20 August 2007

During embryonic development, the anterior-posterior body axis is specified in part by the combinatorial activities of Hox genes. Given the poor DNA binding specificity of Hox proteins, their interaction with cofactors to regulate target genes is critical. However, few regulatory partners or downstream target genes have been identified. Herein, we demonstrate that Hox11 paralogous proteins form a complex with Pax2 and Eya1 to directly activate expression of Six2 and Gdnf in the metanephric mesenchyme. We have identified the binding site within the Six2 enhancer necessary for Hox11-Eya1-Pax2-mediated activation and demonstrate that this site is essential for Six2 expression in vivo. Furthermore, genetic interactions between Hox11 and Eya1 are consistent with their participation in the same pathway. Thus, anterior-posterior-patterning Hox proteins interact with Pax2 and Eya1, factors important for nephrogenic mesoderm specification, to directly regulate the activation of downstream target genes during early kidney development.

Published ahead of print on 4 September 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

Both authors contributed equally to this work.

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• Kutejova, E., Engist, B., Self, M., Oliver, G., Kirilenko, P., Bobola, N. (2008). Six2 functions redundantly immediately downstream of Hoxa2. Development 135: 1463-1470 [Abstract] [Full Text]