Joubert syndrome and Jeune Asphyxiating Thoracic Dystrophy (JATD) are human disorders characterized by multi-organ pathologies including neurocognitive defects, musculoskeletal malformations, respiratory distress and retinal degeneration, among others. Importantly, patients often develop early-onset renal disease due to polycystic or nephronophthisis-like kidney phenotypes, which can progress to end-stage renal failure at a very young age.
These syndromes are caused by genetic mutations that affect proteins essential for the assembly or function of key cellular organelles called the centrosome and primary cilium. One such gene is Cep120, and a new study by researchers in the Division of Nephrology at Washington University School of Medicine gives us new insight into the consequences of Cep120 loss-of-function and its potential implications in cystic kidney disease.
The research group, headed by Assistant Professor of Medicine Moe Mahjoub, PhD, previously showed that Cep120 plays an important role in regulating centrosome biogenesis during cell division. The new study aimed to define the function of Cep120 in cells during quiescence.
“Since the majority of epithelial cells in an adult kidney are in a quiescent state, we wanted to understand how mutations in Cep120 might alter the physiological state or biology of these cells at the molecular level,” says Dr. Mahjoub.
Using cultured mouse and human cells, they showed that Cep120 plays an important inhibitory role at the centrosome during quiescence. Loss of Cep120 disrupted centrosome homeostasis by causing accumulation of a complex of proteins called the pericentriolar material at the centrosome. This in turn resulted in changes to the microtubule-nucleating activities of the centrosome. Consequently, loss of Cep120 function caused defective dynein-dependent protein trafficking to the centrosome, which ultimately resulted in aberrant ciliary assembly and signaling.
The study, which was performed by former Postdoctoral Research Associate and first author, Ewelina Betleja, indicates that there is a Cep120-dependent mechanism that actively regulates centrosome homeostasis in quiescent cells. Disruption of this process is detrimental to the physiology of these cells and the kidney, as loss of ciliary function sensitizes nephron epithelia and causes rapid cystogenesis after renal injury or pharmacological nephrotoxicity.
“Overall, our finding suggest that mutations in Cep120 not only affect renal cells when they are undergoing cell division during development, but can actually make these cells susceptible to cystic transformation when they are in a quiescent state,” say Mahjoub.
The study, A novel Cep120-dependent mechanism inhibits centriole maturation in quiescent cells, is published online in eLife. Authors: Ewelina Betleja, Rashmi Nanjundappa, Tao Cheng and Moe R. Mahjoub.
Visit Dr. Mahjoub’s website and follow him on Twitter @MahjoubLab.