In the Faculty Spotlight
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Jeremy Reiter, MD, PhDPrimary Cilium:
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Some biomedical researchers focus on genes. Others on proteins. For Jeremy Reiter, MD, PhD, Assistant Professor of Biochemistry and Biophysics, the cellular component of choice is the primary cilium. “People have known about this odd organelle for more than a century,” he said. “But until recently, its functions have remained mysterious.”
Looking a bit like a sperm tail, the miniscule apparatus extends off the brain’s neurons, wedged between neighboring cells and generally immobile. Its raison d’être is receiving information from other cells and their environment. Cilia in the retina are photosensitive, allowing us to see; cilia in the nose enable us to smell. Cilia in the kidney are thought to sense the constant flow of urine, bending like reeds in a river; if the kidney is injured and the flow stops, the primary cilium signals the kidney to produce more kidney cells.
And now, as Reiter and a handful of other scientists worldwide are discovering, the primary cilia offers critical insights in the development of stem cells, as well as birth defects and cancers and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
“We’re interested in how cells communicate with each other during development, what kind of signals the cilium conducts, and how human diseases result from those signaling processes gone awry,” he said. “It’s become clear in the last few years that this organelle plays a critical role in fetal development and disease development later in life. If you have defects in the retinal cilia, you get retinal degeneration. If you have defects in kidney cilia, you get polycystic kidney disease.”
Primary cilia play a key role in picking up growth signals, an important process as stem cells differentiate into specialized cells. They carry out this role in a process known as Hedgehog signaling. (The process gets its name from the unusually dense, hedgehog-like pattern of bristles on flies that have a Hedgehog gene mutation.)
The Hedgehog signaling pathway involves a number of proteins that regulate cell proliferation and the development of specific tissues. “Hedgehog is responsible for lots of developmental events, such as determining how many fingers you have and ensuring that your pinkie is different from your thumb,” said Reiter.
Like a car antenna picking up radio signals, the primary cilium appears to be the main site where Hedgehog-related proteins enter the cell and give it instructions. Without a primary cilium, stem cells are unable to “hear” signals that prompt them to differentiate into specific cell types.
Diseases and Potential Cures
The problems occur when genetic mutations cause the Hedgehog signaling pathway to become unregulated. One of the results can be cancer. “Normally, the ‘car radio’ can be turned on and off,” said Reiter. “Here, the radio gets stuck in the ‘on’ position, and to one station that’s telling the cell, ‘Grow, grow, grow!’”
Reiter and his collaborators have found the most direct links between Hedgehog signaling and basal cell carcinoma, the most common form of skin cancer, and medulloblastoma, a highly malignant brain tumor that primarily affects children. Reiter and Arturo Alvarez-Buylla, PhD, Professor of Neurological Surgery, found that basal cell carcinoma and medulloblastoma cancer cells have cilia, and that eliminating cilia through genetic manipulations prevents activation of the Hedgehog pathway, thwarting tumor development. There appear to be more complex connections between malfunctions in the primary cilium and some types of pancreatic and lung cancers.
“Understanding how stem cells interpret signaling cues through the primary cilium is likely to be an important component of learning how to manipulate the signaling pathways well enough to form very specific cells, such as neurons, for cell replacement therapies for diseases like Parkinson’s or Lou Gehrig’s Disease,” says Reiter. When he’s not in the lab, Reiter enjoys rock climbing. He and his wife, Christine Ma, MD, a pediatrician at Children’s Hospital in Oakland, have two children: Kate, 1, and Sam, 4.
Although Reiter has a medical degree as well as a PhD in genetics, both from UCSF, he works full-time as a researcher. “I miss the clinic,” said Reiter. “It was a real privilege and lots of fun taking care of patients. These forays into cancer and Lou Gehrig’s disease are engendered by my medical background, and I hope someday my research will be of direct benefit to human beings.”
Please click here to view Dr. Reiter's faculty bio.
