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Deciphering DiGeorge syndrome


Big advances in understanding microdeletions

A collaboration of European scientists has uncovered new insight into the most common chromosomal microdeletion syndrome in humans. The research group, headed by Dr. Lukas Sommer at the Swiss Federal Institute of Technology, has identified a heretofore unknown role for the TGF cell-to-cell signaling pathway in the pathogenesis of DiGeorge syndrome. By elucidating the genetic mechanism that drives DiGeorge syndrome, Dr. Sommer and colleagues are helping establish a foundation for the future design of therapies to better identify and treat this disease. "We now show that the growth factor TGF is a key signal for normal neural crest development: genetic inactivation of TGF signaling in mouse neural crest stem cells prevents neural crest cell differentiation and recapitulates all morphological features of DiGeorge syndrome," explains Dr. Sommer.

Their report will be published in the March 1 issue of the scientific research journal Genes & Development. DiGeorge syndrome is a congenital disease that annually affects about 1 in 4000 live births. DiGeorge patients display a broad range of symptoms, which may include cardiac defects, immunodeficiency, craniofacial malformations, learning disabilities, and psychiatric problems. DiGeorge patients are generally missing a small portion of chromosome 22. The genes which would normally reside on this area of the chromosome, but which are deleted in DiGeorge patients, direct embryonic development of the pharyngeal arches, an area of the fetus containing so-called "neural crest cells."

The neural crest is a group of cells that, during embryogenesis, segregates into smaller cell clusters and migrate to diverse locations within the embryo. Depending upon location, neural crest cells give rise to most of the peripheral nervous system, as well as various non-neural tissues, like craniofacial bone and cartilage, the thymus and parathyroid glands, and the cardiac outflow tract – in short, all of the tissues that are affected in DiGeorge syndrome.

While embryologists have long known what structures the neural crest contributes to, little is known about the molecular cues that guide this process. Dr. Sommer and colleagues set out to investigate the role of the TGF signaling pathway (already well-known for its role in regulating cell growth and proliferation in other cellular contexts) in the neural crest.

The researchers engineered a strain of mice to specifically lack a TGF receptor in their neural crest stem cells, thereby inactivating TGF signaling in the developing neural crest. Dr. Sommer and colleagues observed that these mice recapitulated all of the defects seen in DiGeorge patients: craniofacial, cardiac, thymic and parathyroid defects.

While neither TGF receptors nor ligands are housed in the deleted region of chromosome 22, Dr. Sommer and colleagues did identify that a protein called CrkL,which is encoded within that region and has been implicated in the development of DiGeorge syndrome, interacts with TGF signaling. The authors speculate that the deletion of CrkL in DiGeorge patients disrupts TGF signal activation and prevents normal development of the neural crest. Dr. Sommer and colleagues not only establish that TGF is a key signal in specifying non-neural cell fates from the neural crest, but they also link defects in TGF signaling to the development of DiGeorge syndrome.

Dr. Sommer is confident that "our mouse model system provides a molecular basis for the clinical findings of DiGeorge syndrome, indicating that TGF signal modulation in neural crest differentiation plays a crucial role in the etiology of this disease."

Heather Cosel | EurekAlert!
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