Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease

Mutations that disrupt centrosome structure or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, it remains unclear how mutations in proteins essential for centrosome biogenesis impact embryonic kidney development. Here, we examined the consequences of conditional deletion of a ciliopathy gene, Cep120, in the two nephron progenitor niches of the embryonic kidney. Cep120 loss led to reduced abundance of both metanephric mesenchyme and ureteric bud progenitor populations. This was due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in filtration function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for branching morphogenesis, cystogenesis and fibrosis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney development, and identifies new therapeutic targets for renal centrosomopathies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/535568v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@198c93forg.highwire.dtl.DTLVardef@1c4750dorg.highwire.dtl.DTLVardef@e0c829org.highwire.dtl.DTLVardef@17512c3_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsDefective centrosome biogenesis in nephron progenitors causes: O_LIReduced abundance of metanephric mesenchyme and premature differentiation into tubular structures C_LIO_LIAbnormal branching morphogenesis leading to reduced nephron endowment and smaller kidneys C_LIO_LIChanges in cell-autonomous and paracrine signaling that drive cystogenesis and fibrosis C_LIO_LIUnique cellular and developmental defects when compared to Pkd1 knockout models C_LI