CONTROL OF CELL DIFFERENTIATION DURING PALATAL FUSION

描述（由申请人提供）：面部发育需要上皮和间质之间一系列复杂的相互作用。不同组的指导性相互作用导致面部原基的模式直接与特定颅面结构的发育和特定细胞的命运相关。二级腭发育有3个特定的模式阶段，即生长带阶段、中线内侧边缘上皮的背-腹侧模式和腭架的前后模式。MEE是背腹型的，一些细胞迁移到口腔或鼻腔表面，而另一些细胞则进行上皮-间充质转分化。MEE的细胞命运是在背-腹方向上建立的，这些命运的调节是高度受控的。腭架的前后模式调节腭融合的时间，并表现出空间上不同的融合事件调节。腭架的生长区、背-腹和前后模式受特定的感应信号的局部调节。TGF-B3已被证明是一个关键的信号分子，在胚胎发生过程中调节MEE的命运，并导致假设；内侧边缘上皮细胞分化受自分泌和旁分泌机制控制，这些机制在腭发育过程中建立生长带、背-腹侧和前后模式。这一假设将通过3个具体目标进行检验；1.确定腭发育生长带期MEE分化的调控因子及其与EGF信号通路的关系；2.表征由细胞粘附分子和生长因子受体定义的腭架融合期间MEE的背-腹侧模式，这些细胞粘附分子和生长因子受体决定了不同MEE群体的具体命运；3)研究确定TGF-B3零突变体Smad 2过表达拯救中完成融合的不同潜力的MEE的前后模式。确定腭融合过程中必不可少的分子机制将导致未来应用于制定产前诊断策略和具体干预措施，以减少人类颅面出生缺陷的发生率。

DESCRIPTION (provided by applicant): The development of the face requires a complex series of interactions between the epithelium and the mesenchyme. The different sets of instructive interactions result in patterning of the facial primordia directly linked to both the development of specific craniofacial structures and the fate of specific cells. Secondary palatal development has 3 specific patterning stages, the growth zone phase, dorsal-ventral patterning of the medial edge epithelium in the midline and the anterior-posterior patterning of the palatal shelf. The MEE are dorsal-ventral patterned such that some cells migrate to the oral or nasal surfaces while others undergo epithelial-mesenchymal transdifferentiation. The cell fate of the MEE is established in a dorsal-ventral orientation and regulation of these fates is highly controlled. Anterior-posterior patterning of the palatal shelves regulates timing of palatal fusion and exhibits spatially distinct regulation of the fusion events. The growth zone, dorsal-ventral and anterior-posterior patterning of the palatal shelves are regulated locally by specific inductive signals. TGF-B3 has been shown to be 1 critical signaling molecule regulating the fate of the MEE during palatogenesis and has led to the hypothesis that; Medial edge epithelial cell differentiation is controlled by autocrine and paracrine mechanisms that establish growth zone, dorsal-ventral and anterior-posterior patterning during palatogenesis. This hypothesis will be tested with 3 specific aims; 1.To determine the factors that regulate MEE differentiation during the growth zone phase of palatogenesis and their relationship to the EGF signaling pathway in these cells; 2.To characterize the dorsal-ventral patterning of the MEE during the fusion of the palatal shelves as defined by cell adhesion molecules and growth factor receptors that determine the specific fates of different populations of MEE; 3) To examine the anterior-posterior patterning of the MEE that defines the different potentials for completion of fusion in the Smad 2 overexpression rescue of the TGF-B3 null mutant. Identification of molecular mechanisms essential to the process of palatal fusion will result in future applications to develop prenatal diagnosis strategies and specific interventions to reduce the incidence of human craniofacial birth defects.