The number of nephrons in a normal kidney shows a wide variation. Low nephron number is correlated with high blood pressure and various renal diseases. In order to generate a sufficient number of nephrons during development, it is critical to balance self-renewal (proliferation) and differentiation (consumption) of nephron progenitors. Self-renewing undifferentiated nephron progenitors express Six2, a transcription factor that is required for the maintenance of the undifferentiated state. Differentiation of these cells involves multiple signaling pathways, two of the most critical being Wnt/beta-catenin and Notch. While Wnt signaling initiates differentiation of the progenitors, Notch signaling is required for further differentiation into proximal tubules. Our recent publication showed that Six2 and Beta-catenin regulate self-renewal and differentiation of nephron progenitors by antagonizing each other through a common set of gene regulatory elements. Still, little is known about the gene regulatory networks regulating the cell fate of nephron progenitors. Our preliminary data suggest that Six2 and Notch2 play important roles during kidney development by regulating expression of common target genes and that Hox proteins participate in the same gene regulatory networks as Notch2. Our goal is to better understand how the cell fate of nephron progenitors is regulated by Six2, Hox, and Notch2, and how nephron progenitors interpret Notch signaling in a context-specific manner through interaction between Notch components and nephron progenitor-specific transcription factors, such as Six2 and HoxD11. To address this, we propose to (1) test the hypothesis that Six2 and Notch2 act as a repressor and an activator, respectively, on common cis-regulatory elements and to (2) test the hypothesis that HoxD11 acts as a mediator of Notch signaling during nephrogenesis. Cell fate decisions of nephron progenitors are determined by complex coordination of multiple transcription factors and signaling pathways. It is critical to identify which target genes are regulated by the transcription factors and to determine how the instructions from various signaling pathways are interpreted by nephron progenitors. Furthermore, understanding how multiple transcriptional regulators downstream of each signaling pathway are orchestrated is essential not only to improve our ability to manipulate nephron progenitors for potential cell replacement therapies but also to develop better ways to prevent or treat renal agenesis or hypoplasia. The results of the proposed research will enhance our knowledge of molecular mechanisms of cell fate decisions and will advance the field of nephrology by providing a better understanding of gene regulatory networks in kidney development. This work is a close collaboration with Steve Potter, an expert in Hox genes, RNA-seq analysis and kidney development, and with Sunghee Oh, an expert in bioinformatics, both my colleagues at Cincinnati Children's Hospital.

Public Health Relevance

Premature depletion of nephron progenitors or defects in nephrogenesis will lead to low nephron number, renal hypoplasia, or renal agenesis. Proper intervention of such problems requires a sound understanding of how nephron progenitors maintain their multipotency and how they differentiate into various types of cells in the nephron. Our preliminary work and proposed research represents an inventive effort to understand gene regulatory networks regulating the cell fate of nephron progenitors. Knowledge gained from this work will provide a novel, genomic perspective on nephrogenesis and organogenesis.

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 (ZRG1)
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Hoshizaki, Deborah K
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Cincinnati Children's Hospital Medical Center
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Marable, Sierra S; Chung, Eunah; Adam, Mike et al. (2018) Hnf4a deletion in the mouse kidney phenocopies Fanconi renotubular syndrome. JCI Insight 3:
O'Brien, Lori L; Guo, Qiuyu; Bahrami-Samani, Emad et al. (2018) Transcriptional regulatory control of mammalian nephron progenitors revealed by multi-factor cistromic analysis and genetic studies. PLoS Genet 14:e1007181
Chung, Eunah; Deacon, Patrick; Park, Joo-Seop (2017) Notch is required for the formation of all nephron segments and primes nephron progenitors for differentiation. Development 144:4530-4539
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Chung, Eunah; Deacon, Patrick; Marable, Sierra et al. (2016) Notch signaling promotes nephrogenesis by downregulating Six2. Development 143:3907-3913
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