Our goal is to elucidate the genetic networks controlled by Eya1 and its cofactors in nephron progenitor cell fate specification, proliferation and differentiation. Eya1 is a transcriptional coactivator that indirectly affects transcription through interaction with DNA-binding proteins. We have shown that Eya1 forms a key transcriptional complex with: (1) the homeodomain transcription factor Six family members Six1/4 to specify the metanephric mesenchyme (MM), and (2) Six2 and Myc in the nephron progenitors to maintain and renew the progenitors. Through mass spectrometry analysis, we have identified the components of the SWI/SNF chromatin remodeling complex as Eya1's interacting proteins. While chromatin remodelers are known to regulate gene expression by altering chromatin structure and facilitating recruitment of essential factors required for transcription, it remains unclear whether the SWI/SNF complex interact with Eya1 as well as other factors to confer specific transcriptional programs that ensure the MM specification and nephron formation. This application proposes to take genetic, genomic, molecular and transgenic approaches to systematically test the hypothesis that Eya1 interacts with the SWI/SNF chromatin remodeling complex and other partner transcription factors to create a combinatorial code that activates gene transcription to specify a nephron fate, dictate the nephron progenitors to either self-renew or undergo differentiation, and determine nephron segmental identity. Specifically, we will characterize the genetic networks controlled by Eya1 and Brg1 in the MM progenitor cell development at different stages. This study will provide a broad view of Eya1-Brg1 association with their targets in Eya1-expressing cells at different stages during nephron formation and provide a rich source for future discovery of cis-regulatory module- associated mechanisms. The information can be used to guide nephron repair and regeneration. This study will provide valuable insights into the genetic networks that underlie congenital nephron deficits.

Public Health Relevance

s: Congenital kidney diseases, including renal agenesis and hypodysplasia, are the most common types of birth defects. This grant proposes to elucidate genetic bases of these congenital diseases and address several key questions of when and how transcription factors interact with chromatin remodeling complexes to mediate a small group of progenitor cells to generate large numbers of individual nephrons (blood-filtering units) in a mature kidney. Understanding how nephron progenitors are specified and maintained may eventually lead to prevention or repair of such renal diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK064640-17
Application #
9968233
Study Section
Kidney Molecular Biology and Genitourinary Organ Development (KMBD)
Program Officer
Hoshizaki, Deborah K
Project Start
2003-08-15
Project End
2022-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
17
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Genetics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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:
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:
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

Showing the most recent 10 out of 17 publications