The long-term objective of this proposal is to elucidate the molecular mechanisms controlling the formation of a functional metanephric mesenchyme during early kidney development by examining the role of the transcriptional coactivator Eya1, its interacting homeodomain protein Six1 and their cofactors. The mammalian kidney develops in a region of posterior intermediate mesoderm by inductive interactions between the metanephric mesenchyme and the ureteric bud epithelium. Recent genetic and molecular studies have indicated that the metanephric mesenchyme may provide initial signals to promote ureteric bud formation. However, what genes and the regulatory hierarchy controlling the formation of the metanephric mesenchyme still remain unclear. Recently, the murine Eya1 gene was found to be expressed in the metanephric mesenchyme and mutations in the human EYA1 gene cause Branchio-Oto-Renal (BOR) syndrome, a congenital birth defect characterized by combinations of branchial, otic and renal anomalies. However, despite the identification of the responsible gene, the developmental and molecular basis for renal defects and the identity of the steps at which Eya1 functions in early kidney morphogenesis are unclear. In Eya1 -/- mice, the metanephric mesenchyme never forms and the mesenchymal cells undergo abnormal apoptosis from E10.5, indicating that Eya1 is a key mesenchymal gene required for early kidney morphogenesis. The homeobox gene Six1 was also found to play an essential role during early kidney development and its gene product physically interacts with Eya1. Moreover, the transcription factor N-myc has been recently isolated through yeast two-hybrid screen using Eya1 as """"""""bait"""""""" and it physically interacts with both Six1 and Eya1 in vitro. Interestingly, mutations in the N-myc gene also cause kidney defects. Based on these data, we hypothesize that these transcription factors function together in the metanephric mesenchyme to regulate early kidney development. This grant will use a powerful genetic system to test this hypothesis and integrate several mesenchymal genes into a genetic and molecular regulatory pathway governing early kidney development. Specifically, I propose to: (1) test the functional role of Eya1 and Six1 during early kidney development, (2) test the possible interactions between Six1, Eya1 and Pax2 in early kidney development, (3) test whether N-myc interacts with Eya1 or Six1 during early kidney development. These studies will clarify the relationship between Pax2, Eya1, Six1, N-myc and other genes, and have a strong likelihood of providing significant insight at the molecular and genetic level into the early developmental process of kidney morphogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064640-03
Application #
6913582
Study Section
Pathology A Study Section (PTHA)
Program Officer
Hoshizaki, Deborah K
Project Start
2003-08-15
Project End
2008-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$272,727
Indirect Cost
Name
Mc Laughlin Research Institute
Department
Type
DUNS #
619471691
City
Great Falls
State
MT
Country
United States
Zip Code
59405
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Li, Jun; Rodriguez, Yoel; Cheng, Chunming et al. (2017) EYA1's Conformation Specificity in Dephosphorylating Phosphothreonine in Myc and Its Activity on Myc Stabilization in Breast Cancer. Mol Cell Biol 37:
Eisner, Adriana; Pazyra-Murphy, Maria F; Durresi, Ershela et al. (2015) The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. Dev Cell 33:22-35
Xu, Jinshu; Xu, Pin-Xian (2015) Eya-six are necessary for survival of nephrogenic cord progenitors and inducing nephric duct development before ureteric bud formation. Dev Dyn 244:866-73
Xu, Jinshu; Wong, Elaine Y M; Cheng, Chunming et al. (2014) Eya1 interacts with Six2 and Myc to regulate expansion of the nephron progenitor pool during nephrogenesis. Dev Cell 31:434-47
Xu, Jinshu; Nie, Xuguang; Cai, Xiaoqiang et al. (2014) Tbx18 is essential for normal development of vasculature network and glomerular mesangium in the mammalian kidney. Dev Biol 391:17-31
Xu, Pin-Xian (2013) The EYA-SO/SIX complex in development and disease. Pediatr Nephrol 28:843-54
Sun, Jianbo; Karoulia, Zoi; Wong, Elaine Y M et al. (2013) The phosphatase-transcription activator EYA1 is targeted by anaphase-promoting complex/Cdh1 for degradation at M-to-G1 transition. Mol Cell Biol 33:927-36
Rinkevich, Yuval; Mori, Taisuke; Sahoo, Debashis et al. (2012) Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nat Cell Biol 14:1251-60
Nie, Xuguang; Xu, Jinshu; El-Hashash, Ahmed et al. (2011) Six1 regulates Grem1 expression in the metanephric mesenchyme to initiate branching morphogenesis. Dev Biol 352:141-51

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