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
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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- "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. "
ABSTRACT: The existence and identification of adult renal stem cells is a controversial issue. In this study, renal stem cells were identified from cultures of clonal human nephrospheres. The cultured nephrospheres exhibited the activation of stem cell pathways and contained cells at different levels of maturation. In each nephrosphere the presence of 1.12-1.25 cells mirroring stem cell properties was calculated. The nephrosphere cells were able to generate three-dimensional tubular structures in 3D cultures and in vivo. In clonal human nephrospheres a PKH(high) phenotype was isolated using PKH26 epifluorescence, which can identify quiescent cells within the nephrospheres. The PKH(high) cells, capable of self-renewal and of generating a differentiated epithelial, endothelial and podocytic progeny, can also survive in vivo maintaining the undifferentiated status. The PKH(high) status, together with a CD133(+)/CD24(-) phenotype, identified a homogeneous cell population displaying in vitro self-renewal and multipotency capacity. The resident adult renal stem cell population isolated from nephrospheres can be used for the study of mechanisms that regulate self-renewal and differentiation in adult renal tissue as well as in renal pathological conditions.Stem Cell Research 08/2013; 11(3):1163-1177. DOI:10.1016/j.scr.2013.08.004 · 3.91 Impact Factor
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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. "
ABSTRACT: The development of the human kidney is a complex process that requires interactions between epithelial and mesenchymal cells, eventually leading to the coordinated growth and differentiation of multiple highly specialized stromal, vascular, and epithelial cell types. The application of molecular biology and immunocytochemistry to the study of cell types involved in renal morphogenesis is leading to a better understanding of nephrogenesis, which requires a fine balance of many factors that can be disturbed by various prenatal events in humans. The aim of this paper is to review human kidney organogenesis, with particular emphasis on the sequence of morphological events, on the immunohistochemical peculiarities of nephron progenitor populations and on the molecular pathways regulating the process of mesenchymal to epithelial transition. Kidney development can be subdivided into five steps: (i) the primary ureteric bud (UB); (ii) the cap mesenchyme; (iii) the mesenchymal–epithelial transition; (iv) glomerulogenesis and tubulogenesis; (v) the interstitial cells. Complex correlations between morphological and molecular events from the origin of the UB and its branching to the metanephric mesenchyme, ending with the maturation of nephrons, have been reported in different animals, including mammals. Marked differences, observed among different species in the origin and the duration of nephrogenesis, suggest that morphological and molecular events may be different in different animal species and mammals. Further studies must be carried out in humans to verify at the morphological, immunohistochemical, and molecular levels if the outcome in humans parallels that previously described in other species. J. Cell. Physiol. 227: 1257–1268, 2012. © 2011 Wiley Periodicals, Inc.Journal of Cellular Physiology 03/2012; 227(3):1257 - 1268. DOI:10.1002/jcp.22985 · 3.87 Impact Factor
Article: RefereeingThe Mathematical Intelligencer 05/1984; 6(2):56-60. DOI:10.1007/BF03024158 · 0.32 Impact Factor