Notch signaling is required for the formation of all nephron segments
Eunah Chung, Ph.D., Patrick Deacon, B.S., Joo-Seop Park, Ph.D..
Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Multipotent nephron progenitors differentiate into distinct segments of the nephron. Different nephron segments perform unique physiological functions. It was previously thought that, in mammals, Notch signaling promotes differentiation of nephron progenitors into proximal tubules, repressing the formation of distal tubules. However, we found discrepancies in the previous studies supporting this model. To investigate if Notch regulates nephron segmentation, we performed Notch loss-of-function and gain-of-function studies in developing nephrons.
Materials & Methods
In order to target developing nephrons in the mouse kidney, we employed Wnt4GFPcre. For Notch loss-of-function study, we deleted Notch1 and Notch2 with Wnt4GFPcre. For Notch gain-of-function study, we conditionally activated expression of an active form of Notch with Wnt4GFPcre or Six2cre. We analyzed nephron segmentation in the mutant kidneys and their controls by performing immunostaining and quantitative PCR.
We found that inhibition of Notch blocks the formation of all nephron segments and that constitutive activation of Notch in developing nephrons does not promote the formation of a specific segment. Furthermore, we found that constitutive activation of Notch in undifferentiated nephron progenitors results in the formation of both proximal tubule and non-proximal tubule cells.
Our data strongly suggest that Notch signaling is required for the formation of all nephron segments and that Notch does not promote proximal tubule formation exclusively. Our work provides a major revision of the previous model. The mechanistic insight from this study has implications for organogenesis and kidney disease.
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