TY - JOUR
T1 - Centrosome amplification disrupts renal development and causes cystogenesis'
AU - Dionne, Lai Kuan
AU - Shim, Kyuhwan
AU - Hoshi, Masato
AU - Cheng, Tao
AU - Wang, Jinzhi
AU - Marthiens, Veronique
AU - Knoten, Amanda
AU - Basto, Renata
AU - Jain, Sanjay
AU - Mahjoub, Moe R.
N1 - Publisher Copyright:
© 2018 Dionne et al.
PY - 2018/7
Y1 - 2018/7
N2 - Centrosome number is tightly controlled to ensure proper ciliogenesis, mitotic spindle assembly, and cellular homeostasis. Centrosome amplification (the formation of excess centrosomes) has been noted in renal cells of patients and animal models of various types of cystic kidney disease. Whether this defect plays a causal role in cystogenesis remains unknown. Here, we investigate the consequences of centrosome amplification during kidney development, homeostasis, and after injury. Increasing centrosome number in vivo perturbed proliferation and differentiation of renal progenitors, resulting in defective branching morphogenesis and renal hypoplasia. Centrosome amplification disrupted mitotic spindle morphology, ciliary assembly, and signaling pathways essential for the function of renal progenitors, highlighting the mechanisms underlying the developmental defects. Importantly, centrosome amplification was sufficient to induce rapid cystogenesis shortly after birth. Finally, we discovered that centrosome amplification sensitized kidneys in adult mice, causing cystogenesis after ischemic renal injury. Our study defines a new mechanism underlying the pathogenesis of renal cystogenesis, and identifies a potentially new cellular target for therapy.
AB - Centrosome number is tightly controlled to ensure proper ciliogenesis, mitotic spindle assembly, and cellular homeostasis. Centrosome amplification (the formation of excess centrosomes) has been noted in renal cells of patients and animal models of various types of cystic kidney disease. Whether this defect plays a causal role in cystogenesis remains unknown. Here, we investigate the consequences of centrosome amplification during kidney development, homeostasis, and after injury. Increasing centrosome number in vivo perturbed proliferation and differentiation of renal progenitors, resulting in defective branching morphogenesis and renal hypoplasia. Centrosome amplification disrupted mitotic spindle morphology, ciliary assembly, and signaling pathways essential for the function of renal progenitors, highlighting the mechanisms underlying the developmental defects. Importantly, centrosome amplification was sufficient to induce rapid cystogenesis shortly after birth. Finally, we discovered that centrosome amplification sensitized kidneys in adult mice, causing cystogenesis after ischemic renal injury. Our study defines a new mechanism underlying the pathogenesis of renal cystogenesis, and identifies a potentially new cellular target for therapy.
UR - http://www.scopus.com/inward/record.url?scp=85055826950&partnerID=8YFLogxK
U2 - 10.1083/jcb.201710019
DO - 10.1083/jcb.201710019
M3 - Article
C2 - 29895697
AN - SCOPUS:85055826950
SN - 0021-9525
VL - 217
SP - 2485
EP - 2501
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 7
ER -