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A large multi-institutional collaboration, including Dr. William Snider’s laboratory, published an article in the Proceedings of the National Academy of Science which identifies a critical component in the development of human syndromes involving craniofacial and cardiac defects. This work began by characterizing patients with craniofacial and cardiac abnormalities akin to those seen in DiGeorge/Velocardiofacial Syndrome. Interestingly, these patients possess a unique deletion encompassing roughly 11 genes, including the ERK2 gene, a key element of the MAP kinase intracellular signaling pathway. The research shows that these patients exhibit reduced expression of ERK2.

A transient, pluripotent cell population known as neural crest contributes to the development of the craniofacial and cardiac structures disrupted in these patients and those with DiGeorge syndrome. Thus, the authors generated mice with deletions of ERK2 and other components of the MAP Kinase pathway, specifically in neural crest. Remarkably, these animals have defects in craniofacial and cardiac development comparable to those seen in the patients. Further work demonstrates that all elements of the MAP kinase cascade, including a downstream transcription factor, SRF, are absolutely necessary for the appropriate development of neural crest derived structures.

Overall, the evidence suggests that of the 11 genes deleted in these patients, ERK2 is most critical. These data provide the first direct evidence for an essential role for MAP kinase signaling in neural crest development in mouse and humans. This work further argues that MAP kinase signaling is part of a common pathway disrupted in other human syndromes involving certain types of craniofacial and cardiac defects. Correcting aberrations in MAPK signaling may represent an interesting therapeutic possibility for future study.

Full Article: http://www.pnas.org/content/105/44/17115.full.pdf+html