The etiology of craniofacial abnormalities is multi-factorial and defects such as cleft palate often occur in the absence of a known cause. Compelling data suggest that inhibin/activin family of proteins is critical for normal craniofacial development and that aberrant production or action of these proteins may have a role in craniofacial defects. Transgenic mice lacking the inhibin/activin betaA gene had severe craniofacial abnormalities that prevented suckling in the pups and led to perinatal death. Knock-out of follistatin also resulted in palate abnormalities, and a subset of mice lacking an activin receptor had skeletal and facial abnormalities similar to that of the human Pierre-Robin syndrome. While activin (beta/beta dimer) was discovered on the basis of its reproductive functions, we now know that this protein, a member of the TGF-beta superfamily, serves as a regulator of growth and differentiations in a variety of cell systems. In particular, activin is critical for mesoderm induction in Xenopus, and activin and follistatin are important in the development and metabolism of bone, a tissue critical for palate formation. Inhibin/activin/follistatin proteins and genes are expressed in a wide spectrum of human fetal tissues. Our preliminary data show that activin protein and activin receptors are present in the developing human fetal palate. Based on these findings, we hypothesize that the inhibin/activin family has a critical role in normal human craniofacial development and that craniofacial malformations can result from deficient production or activity of one or more of these proteins. Since this family has not yet been studied in human craniofacial tissues, the first aim is to elucidate the temporal and regional localization and expression of the inhibin and activin subunits, follistatin and activin receptors throughout normal human craniofacial development using autopsy tissues collected from embryonic through neonatal ages.
The second aim i s to determine whether alterations in mRNA expression, protein biosynthesis, or protein actions for activin, follistatin or activin receptors are associated with cleft palate in humans by comparison with gestational age-matched normal palate tissues. The long term goals of this project are to study the underlying mechanism(s) by which the inhibin/activin family of proteins may lead to craniofacial malformations such as cleft palate, and ultimately to devise a prenatal treatment that may prevent or reverse the malformation.
| Lambert-Messerlian, G M; Pinar, H; Laprade, E et al. (2004) Inhibins and activins in human fetal abnormalities. Mol Cell Endocrinol 225:101-8 |
