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In summary, canonical Wnt signaling plays a central role in the initiation of
nephron progenitor differentiation, whereas the subsequent processes—including
MET and proximo-distal axis formation—are regulated in part by permissive sig-
naling, enabling the self-organization of nephron structure construction. Importantly,
however, the formation of complete nephron structures and their connection with
the urinary exit tracts results from interdependent interactions between the nephron
progenitor, stromal progenitor, and ureteric epithelium. Thus all components of the
metanephric precursors are essential for the construction of well-organized kidney
architecture.
9.4 Definition of Nephron Progenitors
The term “nephron progenitor” refers to cells with the ability to form a nephron. A
genetic lineage tracing study utilizing a tamoxifen-inducible Cre mouse line found
that Six2-positive cells in the MM develop into multiple types of nephron epithelial
cells, including glomerular podocytes and nephric tubules—but not collecting
ducts. Furthermore, transient pulse labeling of Six2-positive cells at E10.5–E11.5
found that they contributed to the E19.5 Six2-positive capping mesenchyme, indi-
cating the capacity to self-renew the nephron progenitors (Kobayashi et al. 2008 ).
However, a recent and more extensive study at a single-cell resolution identified
stage-dependent aging and heterogeneity progression in the cellular population,
suggesting the gradual loss of genuine stem cells (Chen et al. 2015 ). Other detailed
analyses have revealed subpopulations or subdomains within the Six2-positive
nephron progenitors, permitting classification of the population into Cited1+/Six2+
and Cited1−/Six2+ groups (Mugford et al. 2009 ; Brown et al. 2013 ). Nevertheless,
expression of core transcriptional factors such as Six2, Pax2, Wt1, Sall1, Eya1, and
Osr1 is retained within the capping mesenchyme throughout nephrogenesis.
Therefore, these genes are widely accepted as representative markers of nephron
progenitors in mice (Dressler et al. 1993 ; Kreidberg et al. 1993 ; Nishinakamura
et al. 2001 ; Xu et al. 1999 ; James et al. 2006 ). Notably, a recent study concerning
the differential regulation of SIX transcription factors between mouse and human
homologs in the mid-gestation-stage metanephros suggested the existence of differ-
ences in nephron progenitor programs between the species (O'Brien et al. 2016 ).
Indeed, a previous report demonstrated expression of PAX8 in the capping mesen-
chyme of the human embryonic metanephros, while PAX8 expression in the mouse
cap mesenchyme was restricted to differentiated pretubular aggregates or renal
vesicles (Poleev et al. 1992 ). However, the limited accessibility of human fetal kid-
neys renders a comprehensive analysis of renal developmental stages difficult.
Therefore, the criteria which validate genuine human nephron progenitors on the
basis of representative markers remain incompletely understood.
A. Taguchi and R. Nishinakamura