Published Nov. 1, 2016

Researchers have long known that Notch signaling plays a vital role in making nephrons, the functional unit of the kidney.

Furthermore, they generally believed that this signaling regulates which segment of the nephron is formed. The process turns out to be a bit more complicated.

A team of scientists led by Joo-Seop Park, PhD, demonstrated in mice that the differentiation of nephron progenitors requires downregulation of Six2, a transcription factor needed for progenitor maintenance. Notch signaling is necessary for that downregulation.

This finding significantly advances the understanding of kidney development. It also calls into question the generally accepted belief that Notch signaling promotes formation of proximal tubules and represses formation of distal tubules.

“Surprisingly, on the contrary, we found that nephron progenitors lacking Notch genes failed to form distal tubules as well as proximal tubules,” Park says.

This suggests that Notch signaling impacts an earlier step of nephrogenesis, and affects the formation of all nephron segments, not just proximal tubules.

Like other stem cells, nephron progenitors follow one of two paths: either to replicate themselves or differentiate into various types of cells found in the nephron. Both functions help generate sufficient numbers of nephrons before progenitor cells are depleted.

The upshot is that Notch signaling might be a more efficient trigger to induce nephron tubule formation, without biasing the formation of a specific segment of the nephron. Now Park is exploring how nephron progenitors develop into various segments.

“This is a classic stem cell biology question: how does a complex structure such as a nephron develop from one type of progenitor cell population?” he says.