Nephron formation adopts a novel spatial topology at cessation of nephrogenesis

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Australia.
Developmental Biology (Impact Factor: 3.55). 09/2011; 360(1):110-22. DOI: 10.1016/j.ydbio.2011.09.011
Source: PubMed


Nephron number in the mammalian kidney is known to vary dramatically, with postnatal renal function directly influenced by nephron complement. What determines final nephron number is poorly understood but nephron formation in the mouse kidney ceases within the first few days after birth, presumably due to the loss of all remaining nephron progenitors via epithelial differentiation. What initiates this event is not known. Indeed, whether nephron formation occurs in the same way at this time as during embryonic development has also not been examined. In this study, we investigate the key cellular compartments involved in nephron formation; the ureteric tip, cap mesenchyme and early nephrons; from postnatal day (P) 0 to 6 in the mouse. High resolution analyses of gene and protein expression indicate that loss of nephron progenitors precedes loss of ureteric tip identity, but show spatial shifts in the expression of cap mesenchyme genes during this time. In addition, cap mesenchymal volume and rate of proliferation decline prior to birth. Section-based 3D modeling and Optical Projection Tomography revealed a burst of ectopic nephron induction, with the formation of multiple (up to 5) nephrons per ureteric tip evident from P2. While the distal-proximal patterning of these nephrons occurred normally, their spatial relationship with the ureteric compartment was altered. We propose that this phase of nephron formation represents an acceleration of differentiation within the cap mesenchyme due to a displacement of signals within the nephrogenic niche.

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    • "Primers used to evaluate the excision of Dicer exon 24 are listed in Table S6. Section in situ hybridization validation of the microarray was performed as previously described using riboprobes that were PCR-synthesized from wholeembryo cDNA (Rumballe et al. 2011). Sequencing was performed using T7 primers, followed by nucleotide- BLAST to confirm gene specificity. "
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    • "Cessation of nephrogenesis is defined as the final round of new nephron formation in which the last wave of NPCs undergoes mesenchyme to epithelial transition. In the mouse, this occurs shortly after birth and is accompanied by a reduction in Cited1+ cap mesenchyme by P2 (Figure 1B) (Hartman et al., 2007; Rumballe et al., 2011). We reasoned that SMAD1/5 signaling might increase during the terminal phase of nephrogenesis, skewing the renewal versus differentiation balance and depleting the cap mesenchyme. "
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    • "Nephron abundance varies amongst individuals and populations, with a demonstrated influence of genetics and maternal nutritional status on nephron number in humans (Benz and Amann, 2010; Hoy et al., 2006; Luyckx and Brenner, 2010; Wlodek et al., 2008). Self-renewal of NPCs ensures a supply of cells for nephrogenesis until the cessation of nephrogenesis at postnatal day 4 in mice and at 35 weeks of gestation in humans (Hartman et al., 2007; Rumballe et al., 2011). The nephron progenitor niche includes the cap mesenchyme (CM), in which the NPCs reside, and provides extrinsic cues, such as nutrients and morphogens that drive cell intrinsic signaling and metabolic pathways, to promote the availability of NPCs for subsequent nephrogenesis. "
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