Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development

Sun Young Ahn, Yeawon Kim, Sung Tae Kim, Wojciech Swat, Jeffrey H. Miner

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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 formaintaining nephron progenitors. Fgf8 expressionwas 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+/2; Cask2/2 (het/null) kidneys weremoderately 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.

Original languageEnglish
Pages (from-to)1127-1138
Number of pages12
JournalJournal of the American Society of Nephrology
Volume24
Issue number7
DOIs
StatePublished - Jun 28 2013

Fingerprint Dive into the research topics of 'Scaffolding proteins DLG1 and CASK cooperate to maintain the nephron progenitor population during kidney development'. Together they form a unique fingerprint.

  • Cite this