HHMI scientists and colleagues at Johns Hopkins have found a critical clue that helps explain what goes wrong in a key region of the brain at the onset of Down syndrome.

Scientists from the Howard Hughes Medical Institute (HHMI) and Johns Hopkins University School of Medicine have found a critical clue that helps explain what goes wrong in a key region of the brain at the onset of Down syndrome. The work was conducted in mice and is in its early stages, but researchers say it may form the basis for interventions that could mitigate some of the developmental abnormalities in the brain caused by Down syndrome.

Down syndrome is caused when an extra copy of chromosome 21 is present in each of the body's cells. Although the disorder ranks among the most common genetic birth defects, the fine details of the processes that go awry in the developing brain remain murky.

In an article published January 23, 2006, in the online early edition of the Proceedings of the National Academy of Sciences (PNAS), HHMI investigator Philip A. Beachy and colleagues at Hopkins report a role for the protein, Hedgehog, in Down syndrome. Hedgehog is a well-studied protein that initiates communication between cells and plays a fundamental role in determining the form cells assume as they develop. It also helps direct the patterning of tissues and organs in animals, including humans.

“At least some aspects of Down syndrome seem to be explainable as a result of a defect in the ability of these cells to respond to Hedgehog,” said Beachy, referring to a type of neuron known as a granule cell. Beachy and Down syndrome authority Roger H. Reeves and their colleagues studied mice that have an extra chromosome, producing a genetic condition (trisomy) similar to that in human Down syndrome. They discovered that the granule cells in those mice have a blunted response to the critical developmental signaling initiated by Hedgehog.

In humans with Down syndrome, brain volume is reduced. Reeves and his colleagues had previously discovered that this reduction in size and cell number is particularly apparent in the cerebellum. Since much of the development of the cerebellum occurs after birth, this aspect of Down syndrome may be amenable to experimental study. In the new study, Reeves and Beachy compared brain development in newborn trisomic mice to control mice without the condition to determine the earliest point in development at which structural changes occur in the cerebellum.

At birth, trisomic mice with the Down-like condition and control mice have the same number of progenitor granule cells. But those progenitor granule cells in the mice with the Down-like condition were less able to divide and make the granule neurons that form much of the cerebellum. This observation suggested that there might be a deficit in the Hedgehog signaling pathway, which prompts the cells to proliferate. The scientists gathered granule cells from newborn trisomic mice with Down-like syndrome and demonstrated in culture that those cells had a muted response to the protein signal initiated by Hedgehog. As a result, the development and proliferation of the granule cells -- one of the principal cell types in the cerebellum, the part of the brain that coordinates movement and balance -- are suppressed.

Taking the work a step further, the group treated newborn mice in the Down model with an agonist known as SAG1, a drug capable of stimulating the Hedgehog signaling pathway.

The effects, said Beachy, were remarkable: “As you increase the amount of hedgehog protein, the cells divide. They proliferate quite dramatically in response to hedgehog.”

An intriguing but still distant possibility, according to Beachy, would be treating Down syndrome in utero. Down syndrome can be diagnosed in the fetus, and Hedgehog has been shown to have a role in fetal development. “It may be possible to ameliorate Down syndrome with some of these kinds of treatments,” he said.

But while the new study offers a partial explanation about what goes wrong at the outset of Down syndrome, and suggests it may be possible to develop a new class of drugs aimed at mitigating the disorder, more work needs to be done, Beachy said.

For example, while the drug used in the study enhanced the ability of mice with the Down-like syndrome to generate more of the important cells that make up the cerebellum, the practical effects are unknown.

“We don't yet know, for example, if these Down mice experience any functional improvement,” said Beachy.

What's more, issues of safety for manipulating cell communication pathways such as those directed by Hedgehog have yet to be resolved.

“The result here was pretty good,” Beachy explained. "But it also raises a lot of questions. For example, could stimulation of the Hedgehog pathway cause unwanted proliferation in other parts of the brain or in other tissues. More work needs to be done.”

In addition to Beachy and Reeves, Randall J. Roper, Laura L. Baxter, Nidhi G. Saran and Donna K. Klinedinst, all of Johns Hopkins University School of Medicine, were co-authors of the PNAS article.

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