SITE-SPECIFIC MALFORMATIONS IN THE MOUSE EMBRYO

拟议的研究将检验工作假设，即 神经递质5-羟色胺（5-HT）在神经发育过程中起着形态发生信号的作用。 通过激活特定受体和信号的颅面发育 调节细胞增殖、迁移和 其他形态调节分子的表达。血清素能调节 两种生长因子（S-100 β，IGF-II）和粘附相关分子 将在下颌微团培养物中研究腱生蛋白， 使用定量原位杂交和免疫结合的外植体 与软骨核心蛋白相比， 软骨形成对表达5-HT的结构的形态发生的影响 受体和形态调节分子（例如，Meckel氏牙软骨 将在下颌外植体中研究。机制研究 5-羟色胺对脑神经元迁移的剂量依赖性刺激作用 将使用已建立的细胞迁移测定法研究Crest。的 选择性受体激动剂促进迁移的能力将是 与S-100 β（钙离子通道）对神经嵴表达的影响相比， 结合蛋白）和腱生蛋白。细胞的血清素能调节 神经嵴和下颌骨中的增殖和第二信使 将使用3 H-胸苷掺入、cAMP和PI测定培养物 水解测定。这些研究与唐氏症的病因有关 发生特征性颅面畸形的综合征， S-100 β和IGF-II升高，血清素能机制 改变了这项工作也可能提供有关致畸的信息， 5-羟色胺能药物在怀孕期间的潜力。

The proposed studies will test the working hypothesis that the neurotransmitter serotonin (5-HT) acts as a morphogenetic signal during craniofacial development by activation of specific receptors and signal transduction mechanisms that regulate cell proliferation, migration and expression of other morphoregulatory molecules. Serotonergic regulation of two growth factors (S-100beta, IGF-II) and the adhesion-related molecule tenascin will be investigated in mandibular micromass cultures and explants using quantitative in situ hybridization and immunobinding assays, and compared to cartilage core protein, a marker of chondrogenesis. Effects on morphogenesis of structures expressing 5-HT receptors and morphoregulatory molecules (e.g., Meckel's cartilage, tooth germ) will be studied in mandibular explants. Mechanisms underlying the dose-dependent stimulatory effects of 5-HT on migration of cranial neural crest will be studied using an established cell migration assay. The ability of selective receptor agonists to promote migration will be compared to effects on neural crest expression of S-100beta (a calcium binding protein) and tenascin. Serotonergic regulation of cell prolIferation and second messengers in neural crest and mandibular cultures will be determined using 3H-thymidine incorporation, cAMP, and PI hydrolysis assays. These studies are relevant to the etiology of Down's syndrome where characteristic craniofacial malformations occur, levels of S-100beta and IGF-II are elevated, and Serotonergic mechanisms are altered. This work may also provide information regarding the teratogenic potential of Serotonergic drugs during pregnancy.