On October 23rd I presented a Grand Rounds seminar in the Department of Pediatrics at the Medical College of Georgia. In my lecture I conveyed evidence for the extracellular matrix protein fibulin-1 playing a critical role in the formation of the thymus, thyroid, cranial nerves, bones of the skull, blood vessels of the head, aortic arch arteries and outflow tract of the heart. The morphogenesis of all of these tissues involves contributions from a population of cells known as neural crest cells. Disorders of neural crest cells lead to congenital malformations referred to as neurocristopathies. The disorder, DiGeorge syndrome, is a human neurocristopathy having a range of clinical features including hypoparathyroidism, hypoplastic thymus or absent thymus, conotruncal heart defects (e.g., tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, vascular rings) cleft lip and/or palate.
Our research shows that mice deficient in fibulin-1 display many of the abnormalities associated with DiGeorge syndrome. While 90% of individuals with DiGeorge syndrome have a deletion is a region of chromosome 22, specifically the q11.2 region, 10% of DiGeorge patients do not have this deletion. The fibulin-1 gene maps outside of the 22q11.2 region, located at 22q13.2. Ongoing research in my lab has implicated fibulin-1 a regulator of neural crest cell survival and migration during embryonic development. Furthermore, we have evidence that fibulin-1 regulates the expression of several genes previously implicated as being dysregulated in the pathogenesis of DiGeorge syndrome.
