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In a move that bears more than a passing similarity to Woody Allen's movie "Sleeper," where scientists try to clone a dead dictator from his nose, researchers at CUMC and MIT have cloned a mouse from its olfactory neurons.

It's the first time that post-mitotic cells, highly specialized cells that no longer divide, have been used to produce a clone.

The study was the result of a collaboration between the labs of Dr. Richard Axel, University Professor of Biochemistry & Molecular Biophysics and Pathology in the Center for Neurobiology and Behavior, and Dr. Rudolf Jaenisch of the Whitehead Institute for Biomedical Research at MIT, who realized two different questions about development could be answered by one cloning experiment. Their results were published in the March 4 issue of Nature.

During cloning, the nucleus from an adult cell is placed into an egg cell whose nucleus has been removed. The egg is able to erase any changes to the adult cell's chromosomes, returning the chromosomes to a nascent state needed before the clone can develop.

Until now, researchers could only make clones from skin or other cells that can divide. The failures with post-mitotic cells led people to believe that nondividing cells have irreversible changes in their chromosomes that cannot be erased by the egg. Irreversible changes may be caused by additions to chromosomes that can't be removed or DNA rearrangements that remove or scramble parts of chromosomes.

The new experiments show those beliefs were mistaken. By successfully cloning mice from nondividing cells, the researchers demonstrated that any changes to chromosomes in highly specialized, post-mitotic cells are reversible or do not interfere with development of a live mouse.

The finding will now allow researchers to focus on how the egg reprograms the genetic material during cloning, Dr. Jaenisch says. Insights from those studies could be applied to the study of cancer cells, which also reprogram genetic material to turn mature cells into undifferentiated ones.

The findings also answer a question posed by Dr. Axel about how an organism makes a wide variety of neurons. Some scientists have suggested that neuron precursors generate diversity the same way the immune system creates billions of different antibodies: by rearranging pieces of DNA.

The shuffling mechanism is particularly appealing as an explanation for the diversity of olfactory neurons. Each olfactory neuron expresses just one kind of odor receptor, but the choice of receptor seems to be random. The randomness suggested DNA rearrangement was involved in making the choice, since it's the easiest way for the cell to produce random results.

Cloning a mouse from an olfactory neuron was the only way to see if the shuffling hypothesis was correct. If so, all olfactory neurons in a cloned mouse would express the same odor receptor and the mouse would have a very limited sense of smell.

All 40 cloned mice, however, developed normally, with 2 million olfactory neurons expressing a wide variety of odor receptors.

"Now we'll have to go back and find out what mechanisms generate the diversity of olfactory neurons," says one of the lead authors, Dr. Kristin Baldwin, associate research scientist in the Center for Neurobiology and Behavior and Dr. Richard Axel's lab. "Clearly, it's not DNA rearrangement."

The research was supported by the NIH. Dr. Baldwin is an associate and Dr. Axel is an investigator of the Howard Hughes Medical Institute.

—Susan Conova


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