The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage

Department of Developmental Biology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Developmental Biology (Impact Factor: 3.55). 11/2009; 337(2):386-95. DOI: 10.1016/j.ydbio.2009.11.017
Source: PubMed

ABSTRACT We previously determined that Notch2, and not Notch1, was required for forming proximal nephron segments. The dominance of Notch2 may be conserved in humans, since Notch2 mutations occur in Alagille syndrome (ALGS) 2 patients, which includes renal complications. To test whether mutations in Notch1 could increase the severity of renal complications in ALGS, we inactivated conditional Notch1 and Notch2 alleles in mice using a Six2-GFP::Cre. This BAC transgene is expressed mosaically in renal epithelial progenitors but uniformly in cells exiting the progenitor pool to undergo mesenchymal-to-epithelial transition. Although delaying Notch2 inactivation had a marginal effect on nephron numbers, it created a sensitized background in which the inactivation of Notch1 severely compromised nephron formation, function, and survival. These and additional observations indicate that Notch1 in concert with Notch2 contributes to the morphogenesis of renal vesicles into S-shaped bodies in a RBP-J-dependent manner. A significant implication is that elevating Notch1 activity could improve renal functions in ALGS2 patients. As proof of principle, we determined that conditional inactivation of Mint, an inhibitor of Notch-RBP-J interaction, resulted in a moderate rescue of Notch2 null kidneys, implying that temporal blockage of Notch signaling inhibitors downstream of receptor activation may have therapeutic benefits for ALGS patients.

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Available from: Kameswaran Surendran, Sep 15, 2015
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    • "They may also suggest which genes could be involved in stem cell maintenance and differentiation processes in adult kidney. Notch signaling is expressed throughout the development of nephrons (Sharma et al., 2011; Sirin and Susztak, 2012) and the Notch receptors (Notch1 and Notch2) and ligand (Jagged1) involved in kidney development (McCright, 2003; Surendran et al., 2010) are the same as those found upregulated in our nephrospheres. Moreover, the overexpression of genes of Figure 6 In vitro and in vivo formation of three-dimensional tubular-like structures. "
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    • "Podocyte formation occurs during the second stage of glomerulogenesis, when the proximal segment of the S-shaped body differentiates to form the parietal (Bowman capsule) and the visceral (podocytes) epithelium [18]. Notch signaling controls segmentation of the comma-shaped body and generation of the S-shaped body, which further differentiates to form podocytes [22]. Signal transduction is initiated by engagement of the plasma membrane Notch receptors expressed on the signal-receiving cells with ligands anchored at the plasma membrane on signal-sending cells. "
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    • "Recent data from our group clearly show the expression in the Comma-and s-shaped bodies of thymosin Beta 10, a member of beta thymosins, a family of peptides which play essential roles in many cellular functions (Gerosa et al., 2010). Notch1, in concert with Notch2, has been shown to contribute to segmentation of the Comma-shaped body and to the origin of the S-shaped body (Surendran et al., 2010), which has been demonstrated to be organized into three segments, proximal, medial, and distal: the cells of the proximal segment further differentiate to form the parietal (Bowman capsule) and visceral (podocytes) epithelium of the glomerulus; those of the median segment give rise to the proximal tubules, whereas those of the distal segment drive the process of fusion with the collecting tubules (Georgas et al., 2009; Fig. 13). The third stage, the capillary loop stage, is characterized by the appearance and development in the renal cortex of the primitive loop of Henle. "
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