Myc in nervous-system development

Scientists have long known that neuroblastoma, a childhood cancer of the nervous system, overproduces one form of Myc. Yet Myc's normal role in nerve and brain development has been unclear.

"Many labs have focused on Myc overproduction in neuroblastoma," said Dr. Paul Knoepfler, postdoc in the Eisenman lab.

"We thought, let's take a different approach and ask, what is Myc's function in establishment of the nervous system?"

To tackle this question, Knoepfler and staff associate Pei Feng Cheng used a strategy favored by geneticists: Take something away and see what happens.

The problem, Knoepfler said, is that mice can't survive without Myc, making it difficult to gain much insight by studying animals known as knockout mice that lack Myc entirely.

But new techniques permit researchers to shut off production of a protein of interest in a specific tissue or organ.

"This is a really powerful approach," he said. "It allowed us to conduct the first analysis of the normal function of any form of Myc in a developing organ system."

When Knoepfler examined mice whose nervous tissue lacked N-Myc, the predominant form of Myc expressed in the developing nervous system, he observed several abnormalities.

Most striking was a two-fold reduction in overall brain size in the Myc-deficient animals. The cerebellum, the part of the brain that controls motor function, was six times smaller in the mutant mice.

As a result, the mice were deficient in coordination and exhibited behavioral abnormalities such as excessive digging.

Knoepfler found that the reduced size of the cerebellum was likely due to a reduction in both the number and size of nervous-system progenitor cells, a group of dividing cells that spawn specialized (nondividing) cells characteristic of each part of the organ.

He suspects that loss of Myc in the nervous system forces the progenitor cells to prematurely differentiate, which results in a smaller pool of specialized cells.

The profound effects of Myc loss on the cerebellum have important implications for the study of a childhood cancer called medulloblastoma, which is thought to arise from cells in this part of the brain, Knoepfler said.

"If we can dissect out the Myc pathway," he said, "it may ultimately lead to strategies to compensate for abnormal Myc function in this type of cancer."