A New Paradigm for Understanding Nephron Formation
Published December 15, 2017 | Development
Researchers at Cincinnati Children’s discovered in 2016 that Notch signaling plays an early, critical role in nephrogenesis. Now, a follow-up study shows that its role extends beyond the early stages of nephron formation to the formation of all nephron segments.
Their discovery revises a decade-old understanding of Notch signaling and represents a big step toward generating functional nephrons, a potential treatment for kidney disease.
In the 2016 study, a team of scientists led by Joo-Seop Park, PhD, found that Notch signaling is responsible for turning off the gene Six2, an essential step in nephrogenesis. They also established that removing Notch genes in undifferentiated nephron progenitor cells blocked nephron formation before the process of nephron segmentation started. In the 2017 follow-up study, co-authored by Park, Eunah Chung, PhD, Patrick Deacon, research assistant, the team genetically manipulated Notch signaling in differentiating nephron progenitor cells that were undergoing nephron segmentation.
“When we blocked Notch signaling, no nephron was formed, suggesting that Notch signaling is continuously required for nephron formation during differentiation,” says Park. “When we activated Notch signaling in differentiating nephron progenitors, properly segmented nephrons still formed, strongly refuting the previous model that Notch signaling promotes the formation of the proximal tubules and represses the formation of the distal tubules.”
Furthermore, the team found that Notch signaling regulates the expression of key transcription factors known to be required for differentiation of nephron progenitors.
“These results suggest that Notch signaling primes nephron progenitors for differentiation, rather than directing their cell fates into proximal tubules,” Park explains. “The next step in our quest to generate functional nephrons is to investigate other signaling pathways that potentially regulate mammalian nephron segmentation.”
