Inhibin/Activin Family in Human Cranifocial Development

颅面畸形的病因是多因素的，腭裂等缺陷经常在没有已知原因的情况下发生。令人信服的数据表明，抑制素/激活素蛋白家族对颅面正常发育至关重要，这些蛋白的异常产生或作用可能在颅面缺陷中起作用。缺乏抑制素/激活素β a基因的转基因小鼠有严重的颅面异常，导致幼鼠无法哺乳并导致围产期死亡。敲除卵泡抑素也会导致上颚异常，缺乏激活素受体的一小部分小鼠骨骼和面部异常，与人类皮埃尔-罗宾综合征相似。激活素（β / β二聚体）是在其生殖功能的基础上被发现的，我们现在知道这种蛋白质是tgf - β超家族的成员，在多种细胞系统中作为生长和分化的调节剂。特别是，激活素对非洲爪蟾的中胚层诱导至关重要，激活素和卵泡抑素在骨骼的发育和代谢中很重要，而骨骼是腭形成的关键组织。抑制素/激活素/卵泡抑素蛋白和基因在广泛的人类胎儿组织中表达。我们的初步数据表明，激活素蛋白和激活素受体存在于发育中的人类胎儿腭。基于这些发现，我们假设抑制素/激活素家族在正常人类颅面发育中起关键作用，颅面畸形可能是由于一种或多种这些蛋白质的产生或活性不足造成的。由于该家族尚未在人类颅面组织中进行研究，因此第一个目的是阐明抑制素和激活素亚基、卵泡抑素和激活素受体在正常人类颅面发育过程中的时间和区域定位和表达，使用从胚胎到新生儿年龄收集的尸检组织。第二个目的是通过与胎龄匹配的正常腭裂组织比较，确定mRNA表达、蛋白质生物合成或激活素、卵泡抑素或激活素受体的蛋白质作用的改变是否与人类腭裂有关。该项目的长期目标是研究抑制素/激活素家族蛋白可能导致颅面畸形（如腭裂）的潜在机制，并最终设计出可能预防或逆转畸形的产前治疗。

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 is 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.