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Abstract: FR-OR045

Inactivation of Foxi1 Rescues Most of the Hes1-Deficient Mouse Kidney Collecting Duct Defects

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 501 Development, Stem Cells, and Regenerative Medicine: Basic


  • Mukherjee, Malini, Sanford Research / University of South Dakota, Sioux Falls, South Dakota, United States
  • DeRiso, Jennifer, Sanford Research, Sioux Falls, South Dakota, United States
  • Surendran, Kameswaran, Sanford Research / University of South Dakota, Sioux Falls, South Dakota, United States

The distal nephron and collecting duct segments of mammalian kidneys consist of intercalated cell types intermingled among Aqp2-expressing (principal) cell types. Notch signaling ensures that a sufficient number of cells select the Aqp2-expressing instead of an intercalated cell state. However, the precise mechanisms by which Notch patterns the collecting ducts is unknown. Here we tested whether Notch signaling simply represses Foxi1, an essential intercalated cell specific transcription factor, to allow for principal cell differentiation.


Hes1, a direct target of Notch signaling, was inactivated in developing kidney distal nephron and collecting duct segments by generating Cdh16-Cre;Hes1f/f mice and compared with Cdh16-Cre;Hes1f/f;Foxi1-/- mice to determine whether the only function of Notch in developing collecting ducts is to repress Foxi1. We also tested whether Hes1 directly regulates principal cell genes in a calcium/calmodulin-dependent protein kinase-II (CaMKII) in ex vivo embryonic kidney cultures.


Inactivation of Hes1 resulted in fewer principal cells, and reduced principal cell specific gene expression, and ability to concentrate urine, along with increased expression of Foxi1. Inactivation of Foxi1 rescues the Hes1-deficient principal cell deficiency and the ability to concentrate urine. However, detailed examination of Cdh16-Cre;Hes1f/f;Foxi1-/- mouse kidneys revealed reduced expression of certain principal cell (PC) specific genes. Consistent with PC specific genes being regulated independent of Foxi1, Foxi1 inactivation in mice does not result in increased expression of all PC specific genes. Additionally, Hes1 and PC specific genes are down-regulated upon inhibition of Notch signaling in cultured principal cells without activation of Foxi1 expression. Hes1 can directly activate proximal promoters of Aqp2, Aqp3 and Elf5 in a CaMKII sensitive manner. The expression of PC specific genes and not Foxi1 expression is dependent on CaMKII activity in ex vivo mouse embryonic kidney cultures.


Notch/Hes1 has at least two roles during collecting duct development: (i) principal cell fate selection by repressing Foxi1 expression and (ii) activation of principal cell gene expression in a CaMKII dependent manner.


  • NIDDK Support