by Jim Fessenden
UMass Chan Medical School
New research by Sumeda Nandadasa, PhD, reveals how a key protein associated with Meckel-Gruber syndrome, nephronophthisis, Joubert syndrome and other ciliopathies is cut in half to perform two separate functions, both of which are fundamental to the healthy development of children. These findings, published in Nature Communications , shed new light on how cilia formation and cell signaling are finetuned by forces acting outside of a cell and may have potential implications for the treatment of related ciliopathies.
"Patients with a genetic mutation of TMEM67 develop severe ciliopathies affecting normal embryonic and neonatal development, but until now we had absolutely no idea how exactly this molecule worked," said Dr. Nandadasa, assistant professor of pediatrics. "What we've done is identify a cut, or cleavage, that happens to the protein with one aspect controlling development of cilia and the other acting on cell signaling."
Small antenna-like structures that protrude from nearly all eukaryotic cells, cilia are essential for movement, signaling, sensing mechanical stimuli and controlling fluid flow.
"Abnormal development of cilia affects all aspects of life including sperm motility, photoreceptors in the retina and olfactory neurons in the nasal epithelia," according to study co-author Manu Ahmed, PhD, a postdoctoral fellow in the Nandadasa lab. "Additionally, the epithelia lining of the kidney tubules, brain ventricles, oviducts and trachea all heavily depend on cilia."
Genetic mutations that lead to defects in the structure or function of cilia make up a group of diseases classified as ciliopathies. When cilia become compromised, cells are unable to sense and integrate signals and stimuli from the environment. This leads to syndromic ciliopathies, such as Bardet-Biedl syndrome, polycystic kidney disease, Joubert syndrome and many others.
Mutations to TMEM67 is the leading cause of Meckel-Gruber syndrome, the most severe form of ciliopathy in humans with a 100 percent fatality. However, the mechanisms behind how TMEM67 mutations cause the disease are poorly understood. Adding to the mystery, TMEM67 performs two different functions in different parts of the cell.
Using a combination of proteomics and mass spectrometry to identify where and how proteins are cut, Nandadasa and colleagues have shown that TMEM67 is cut at a very specific spot—not just in mice models, but in the nematode C. elegans and human cells, as well.
After the TMEM67 protein is cut, the two resulting halves, called isoforms, have very specific functions. One becomes a key protein for cilia development. It migrates along the cell surface to a specialized gate-keeping structure formed at the base of the cilium. Once there, it regulates the entry and exit of molecules separating the ciliary compartment from the cell's cytoplasm and membrane, like a revolving door.
In mutated forms, the protein remains uncut. As a result, this gate is dysfunctional and impairs the proper development and building of cilia. These cilia can be highly dysmorphic, sometimes ballooning out like ears or satellite dishes.
Meanwhile, the noncleaved TMEM67 isoform is critical for transducing the noncanonical Wnt pathway and is essential for normal Wnt signaling in the cell.
This confluence between species and human disease highlights the evolutionary importance of this process in the formation and functioning of cilia.
"Now that we have a clearer picture of what part of this molecule does what job, we can begin investigating how the two parts work independently and possibly develop new interventions for patients with ciliopathies caused by mutations of TMEM67," said study coauthor Sydney Fischer, a PhD candidate in the Morningside Graduate School of Biomedical Science.
About UMass Chan Medical School
UMass Chan Medical School, one of five campuses of the University of Massachusetts system, comprises the T.H. Chan School of Medicine; the Morningside Graduate School of Biomedical Sciences; the Tan Chingfen Graduate School of Nursing; ForHealth Consulting at UMass Chan Medical School, a public service health care consulting division; and MassBiologics, the only nonprofit, FDA-licensed manufacturer of vaccines, biologics and viral vector gene therapies in the United States; and a thriving Nobel-Prize-winning biomedical research enterprise.
UMass Chan is advancing together to improve the health and wellness of our diverse communities throughout Massachusetts and across the world by leading and innovating in education, research, health care delivery and public service. UMass Chan has built a reputation as a world-class destination for biomedical research. It is ranked among the best medical schools in the nation for primary care education and biomedical research by U.S. News & World Report. In 2021, the Medical School received a $175 million gift from The Morningside Foundation and was renamed UMass Chan Medical School. Learn more at www.umassmed.edu .
