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Multiplying neurons – This image shows two horizontal neurons that were derived from a single neuron by modulating the Rb family of tumor suppressor gene. PHOTO COURTESY ST. JUDE CHILDREN’S RESEARCH HOSPITAL

Researchers at St. Jude Children’s Research Hospital have recently published a study which reveals the genes responsible for retinoblastoma have the ability to mutate in way never before thought possible.

This certain type of mutation enables specific cells in the retina to multiply and cause eye cancer, a discovery that suggests deliberate genetic manipulations might coax an injured brain to repair itself.

Retinoblastoma arises in the retina — the multi-layered, membrane lining the back of the eye that responds to light by generating nerve impulses that are carried to the brain by the optic nerve. It was previously thought that retinoblastoma arose from immature, progenitor cells.

The immediate importance of the St. Jude finding, a study that was conducted on mice, is that it unexpectedly showed that retinoblastoma can, in fact, arise from fully matured nerves in the retina called horizontal interneurons, explained Michael Dyer, PhD, associate member of the St. Jude department of developmental neurobiology. This disproves a more than 100-year-old scientific principle that fully formed, mature nerves cannot multiply like young, immature cells.

This is the first example ever discovered of mature nerve cells dividing in any system of the body, a finding that has much broader implications for science.

“The key next step, which we’re working on now,” Dyer said, “is (determining whether) this is just one kind of neuron we just happened upon or is this something we can induce in any nerve that we need to depending on the type of degeneration occurring elsewhere in the brain.”

Dyer’s group made their discovery by developing different populations of mice whose retinas lacked one or more members of the Rb family of genes that include Rb, p107 and p130. The fact that mature cells divided in this experiment suggests these key genes involved with retinoblastoma are the ones to manipulate, Dyer explained, if scientists want to someday make other neurons divide to replace those lost to degeneration.

If the horizontal interneuron cell division was allowed to proceed unchecked, highly differentiated tumors formed that resembled normal horizontal neurons. Unexpectedly, these tumors were aggressive and spread rapidly.

This has led St. Jude investigators to begin new studies developing a way to control mature cell division to be able to make the right amount of neurons to fight the cancer.

It also raises questions about the conventional wisdom surrounding cell differentiation in tumors. Differentiation is the process by which cells lose their primitive, stem-cell-like properties that include the ability to grow and multiply, and instead develop specialized shapes and functions. The discovery that fully differentiated horizontal interneurons can multiply to form retinoblastoma challenges the established scientific belief that cancer cells are most aggressive when they are undifferentiated. For example, the leukemic cells of chronic myelogeneous leukemia (CML) are much less aggressive when they are differentiated.

“I’m not saying anyone is going to rule anything out but (this discovery) will make us more cautious about treatments that induce tumor differentiation,” Dyer said.

Another major implication of this finding affects the world of stem-cell biology. The ability of mature cells to divide suggests that if researchers were able to alter the activity of certain genes in fully developed neurons, they might be able to trigger them to multiply temporarily and replace the neighboring neurons that were lost as a result of neurodegenerative diseases such as Alzheimer’s, Dyer said.

Stem cell biology has many challenges before successful treatment can be developed. Currently, the approach is to take neural or any type of stem cells, inject them directly into the brain of someone with a degenerative disorder like Alzheimer’s or Parkinson’s, and hope that the cells first make the right type of neuron and secondly, make the right connections in the brain circuitry.

“What we found is, if you change these certain proteins in the nerve cells themselves, they can divide and make more nerves,” Dyer explained. “Having nerves duplicate themselves might be more efficient than trying to stimulate nerve replacement by inserting stem cells into the brain, since the existing nerves would already be in the right place to restore missing brain cells. However, there’s still a lot of research required to determine if it is possible to control gene activity to make this approach practical.

“We have an additional goal which is, ‘can you develop a drug that could make this happen?”

It’s an alternative approach that the study just opened the door to, Dyer said, because before now there was no way to study it.

Two projects have arisen from this study, the first of which is trying to determine if this process of making nerves divide can be broadly applicable. The second is related to understanding the differentiation and tumor metastasis for retinoblastoma.

“This opens an exciting new chapter in the study of neurons and brain tumors,” he said.



January 2008

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