In the U.S., 1,000 to 2,000 children are born with anencephaly each year. Most do not survive more than a day or two. Although anencephaly can sometimes be diagnosed through ultrasound, which picks up the malformation of the head, there is no genetic test, and its cause is unknown. By breeding special "knockout" mice that were missing the gene for the enzyme called HSD17b7, UIC researchers found that such mice died on the tenth day of gestation with the severe lack of brain development that characterizes the human birth defect.

The failure of the mice to develop, as well as the extreme changes in the formation of the animals, was very surprising, said Geula Gibori, UIC distinguished professor of physiology and biophysics and principal investigator of the study. Mice that lack enzymes of similar function are born with subtle changes in their cognitive ability, but they survive. The UIC researchers had Previous UIC research had discovered this novel enzyme and focused on its role in converting the weak hormone estrogen into the more potent estradiol in the ovaries and its possible role in breast cancer.

Recent research has shown that the HSD17b7 enzyme has an additional role in the last steps of cholesterol biosynthesis. But because the fetus receives cholesterol from the mother during gestation, Gibori and her colleagues did not expect the enzyme to be of much importance to development. However, it appears that as the fetal mouse brain develops it forms a blood barrier, blocking maternal cholesterol from brain cells. The brain becomes dependent on the biosynthesis of its own cholesterol once this blood-brain barrier forms, at day 10 of gestation.

The UIC researchers established that in the fetus, the brain is the most important site for HSD17b7 expression and provided evidence that anencephaly may result from the loss of this enzyme. "Creating a knockout mouse is a very laborious process," said Aurora Shehu, first author of the paper and at that time a graduate student in Gibori's laboratory. Mice with only one copy of the gene are produced and then interbred; one in four of their offspring should have no copy of the gene - a "null" mouse.

"We expected null mice to be born and to be infertile, however, no null mice were born," said Shehu. "I was afraid I had made a mistake, and went back to the beginning, repeating the entire process, but still no null mice were born." Shehu then began more painstaking work, performing in-utero genetic testing on entire litters - often 10 to 12 fetuses per litter. She found that the null mice were there, but they were dying at day 10 of gestation, when the blood-brain barrier develops.

Gibori says the gene that is missing or defective in human anencephaly is not yet known, but the discovery that the deletion of HSD17b7 in the mouse causes anencephaly suggests this gene may be awry in the human disease. "This opens up very exciting possibilities for understanding human anencephaly, and, perhaps, someday being able to provide a genetic test for the condition early in pregnancy - and ultimately a therapy," she said. As their next step, Gibori's lab plans to test human anencephalic tissue for a mutation in the HSD17b7 gene.

Good Communication Between Neurons and Muscle Cells
You can't raise a finger without your brain directing muscle cells, and scientists have figured out another reason that usually works so well. A neuron sends a message, or neurotransmitter, to the muscle cell to tell it what to do. To get the message, the receiving cell must have a receptor. Oddly, the unstable protein rapsyn is responsible for anchoring the receptor so it's properly positioned to catch the message.

Medical College of Georgia scientists have found what keeps rapsyn in proper conformation. It is a heat shock protein, one of a large family of molecular chaperones that make sure proteins get where they are needed and do what they should, says Dr. Lin Mei, chief of developmental neurobiology at MCG and Georgia Research Alliance Eminent Scholar in Neuroscience.

Hsp90β helps stabilize rapysn so receptors can get and stay where needed, according to research published in the Oct. 9 issue of Neuron. Dr. Mei suspects that other hsp siblings have a similar caretaker role in neuron-to-neuron communication in the brain.

Scientists knew rapsyn's role in getting neuromuscular receptors to aggregate and stay where needed, but they didn't know what stabilized it. "It makes you wonder how to control this naughty boy which is very important," says Dr. Mei, the study's corresponding author. They found hsp90β wherever rapsyn clustered in muscle cells. When they disrupted its activity or expression, they realized hsp90β's stabilizing role in forming and maintaining receptor clusters, says Dr. Shiwen Luo, postdoctoral fellow in Dr. Mei's lab and the study's first author. Rapsyn and the receptor apparently interact, then hsp90β comes along to help stabilize the relationship.

Rapsyn mutations have been implicated in muscular dystrophies including congenital myasthenia gravis. MCG researchers are looking now to see if a mutated rapsyn still interacts with hsp90β.

They used a type of acetylcholine nicotinic receptor at the neuromuscular junction as a model for their studies of brain development and communication. The junction is 1,000 times larger than connections, or synapses, between two neurons but structurally similar. Fundamentals include presynaptic terminals that release neurotransmitters picked up by receptors on the postsynaptic side. Terminals and receptors must be lined up well, whether it's a muscle cell or neuron getting the message. "In central nervous system synapses and at the neuromuscular junction, receptors have to be concentrated at the right spot to receive the neurotransmitter released," says Dr. Mei. If receptors are in the wrong place, the message can be weak or even lost.

At the neuromuscular juncture, communication is usually straightforward, with primarily one neurotransmitter and one principal receptor. "Whenever you tell a muscle to move, it moves. If you want your muscles to think, you wouldn't be able to pick up a pin," says Dr. Mei. In the brain, where neurons have thousands of synapses, it's more of a negotiation. "Signals have to be integrated in the neuron for it to decide what to do."

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