The goal of this project is to elucidate the mechanisms by which EYA1 controls nephron progenitor cell development in the mammalian kidney. In mammals, kidney development involves the specification of the metanephric mesenchyme (MM), the outgrowth of the ureteric bud (UB), and reciprocal interactions between the UB and the MM to generate large numbers of nephrons as well as the renal collecting system in the mature kidney. Mutations in genes that disrupt these processes cause renal agenesis and hypoplasia. We and others identified EYA1 and its cofactor SIX family proteins as critical mesenchymal factors for kidney development. Defects in these genes in humans cause Branchio-Oto-Renal (BOR) syndrome, a congenital birth defect characterized by a combination of branchial, otic and renal anomalies. To understand the basis of kidney defects that occur in BOR syndrome, we analyzed EYA1 and SIX1/5 mutations identified from patients and generated knockout mice. Our results show that these genes interact and are essential for MM cell development and UB branching. Since the MM is not formed in Eya1-/- mice, we have recently generated Eya1flox and Eya1CreERT2 alleles. We found that deletion of Eya1 after UB outgrowth results in depletion of the MM progenitors due to premature epithelialization and that EYA1 directly interacts with SIX2 and Myc family proteins, which are known to be important for the maintenance of the MM progenitors. Our analyses indicate that EYA1 dephosphorylates Myc at Thr58 to prevent the Myc protein from degradation in vitro and that deletion of Eya1 in the MM cells leads to increased levels of phosphor-T58-Myc but decreased levels of Myc. Currently, however, we do not understand how these key factors are functionally linked to regulate the proliferation and maintenance of the nephron progenitors. In this renewal application, we propose to take a combination of molecular, biochemical, genetic and genomic approaches to test the hypothesis that EYA1, Myc and SIX2 interact to regulate the expansion of the nephron progenitor pool and identify the target genes that are controlled by EYA1 and its cofactors. This study should advance the field by revealing novel mechanisms of how EYA1 interacts with its cofactors to regulate self-renewal of the nephron progenitors.

Public Health Relevance

Congenital kidney diseases, including renal agenesis and hypodysplasia, are the most common types of birth defects. This grant proposes to elucidate the genetic bases of these congenital diseases and address several key questions of when and how a set of transcription factors act to mediate a small group of progenitor cells to generate large numbers of individual nephrons (blood-filtering units) in a mature kidney. Identifying the genes and understanding their roles and functions in the nephron progenitor/stem cells may eventually lead to prevention or repair of such renal diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (KMBD)
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Hoshizaki, Deborah K
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
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Zhang, Haoran; Wang, Li; Wong, Elaine Yee Man et al. (2017) An Eya1-Notch axis specifies bipotential epibranchial differentiation in mammalian craniofacial morphogenesis. Elife 6:
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; 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, 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, 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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