Reciprocal signaling between progenitor cells of the stromal mesenchyme (SM), metanephric mesenchyme and ureteric bud is critical for proper mammalian kidney morphogenesis. Several of these signaling pathways are regulated by the centrosome, and its associated structure the primary cilium. Mutations in genes that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and lead to cystic-fibrotic pathologies. Yet, it remains unknown how mutations in centrosome genes impact renal interstitial progenitor cell physiology. Here, we examined the consequences of defective centrosome biogenesis on SM progenitor cell growth, differentiation, and fate. Conditional deletion of Cep120, a ciliopathy gene essential for centrosome duplication, in the stromal mesenchyme resulted in reduced abundance of pericytes, interstitial fibroblasts and mesangial cells at birth. These phenotypes were caused by a combination of delayed mitosis, increased apoptosis, as well as changes in Wnt and Hedgehog signaling pathways essential for differentiation of stromal lineages. Cep120 ablation resulted in small hypoplastic kidneys with medullary atrophy and delayed nephron maturation. Finally, Cep120 and centrosome loss in the interstitium sensitized kidneys of adult mice, causing rapid fibrosis via enhanced TGF-β/Smad3-Gli2 signaling after renal injury. Our study defines the cellular and developmental defects caused by centrosome dysfunction in embryonic kidney stroma.
Ewa’s new preprint about the effects of Cep120/centrosome loss in the kidney stromal progenitors is now on bioRxiv
