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2013 ; 24
(7
): 1127-38
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Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor
population during kidney development
#MMPMID23661808
Ahn SY
; Kim Y
; Kim ST
; Swat W
; Miner JH
J Am Soc Nephrol
2013[Jun]; 24
(7
): 1127-38
PMID23661808
show ga
DLG1 (discs-large homolog 1) and CASK (calcium/calmodulin-dependent serine
protein kinase) interact at membrane-cytoskeleton interfaces and function as
scaffolding proteins that link signaling molecules, receptors, and other
scaffolding proteins at intercellular and synaptic junctions. Dlg1-null mice
exhibit hydronephrosis, hydroureter, and occasionally hypoplastic kidneys,
whereas Cask-null mice do not. To investigate whether DLG1 and CASK cooperate in
the developing urogenital system, we generated mice deficient in both DLG1 and
CASK either 1) globally, 2) in metanephric mesenchyme, or 3) in nephron
progenitors. With each approach, Dlg1;Cask double-knockout (DKO) kidneys were
severely hypoplastic and dysplastic and demonstrated rapid, premature depletion
of nephron progenitors/stem cells. Several cellular and molecular defects were
observed in the DKO kidneys, including reduced proliferation and increased
apoptosis of cells in the nephrogenic zone and a progressive decrease in the
number of cells expressing SIX2, a transcription factor essential for maintaining
nephron progenitors. Fgf8 expression was reduced in early-stage DKO metanephric
mesenchyme, accompanied by reduced levels of components of the Ras pathway, which
is activated by fibroblast growth factor (FGF) signaling. Moreover,
Dlg1(+/-);Cask(-/-) (het/null) kidneys were moderately hypoplastic and
demonstrated impaired aggregation of SIX2-positive cells around the ureteric bud
tips. Nephron progenitor-specific het/null mice survived with small kidneys but
developed glomerulocystic kidney disease and renal failure. Taken together, these
results suggest that DLG1 and CASK play critical cooperative roles in maintaining
the nephron progenitor population, potentially via a mechanism involving effects
on FGF signaling.