CONTROL OF CELL DIFFERENTIATION DURING PALATAL FUSION

描述（由申请人提供）：面部的发育需要上皮和间充质之间的一系列复杂的相互作用。不同的指导性相互作用导致面部原基的图案化，这些图案化直接与特定颅面结构的发育和特定细胞的命运相关。腭的发育有3个特定的模式化阶段，即生长区阶段、中线内侧缘上皮的背腹模式化和腭架的前后模式化。这些细胞是背腹型的，使得一些细胞迁移到口腔或鼻腔表面，而另一些细胞经历上皮-间充质转分化。细胞的命运，建立在背腹方向和调节这些命运是高度控制。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的调节。腭架的生长区、背腹和前后模式由特定的诱导信号局部调节。TGF-β 3已被证明是一个关键的信号分子调节腭发育过程中的腭的命运，并已导致的假设，内侧边缘上皮细胞分化是由自分泌和旁分泌机制，建立生长区，背腹和前-后腭发育过程中的图案。本研究将从三个方面对这一假说进行验证：1.确定在腭发育的生长区阶段调控腭突分化的因素及其与这些细胞中EGF信号通路的关系; 2.背侧肌的特征-在腭架融合过程中，由细胞粘附分子和生长因子受体确定的腹侧模式决定了不同种群的特定命运的; 3）检查在TGF-β 3无效突变体的Smad 2过表达拯救中定义完成融合的不同潜力的前-后模式。腭融合过程中必不可少的分子机制的鉴定将导致未来的应用，以制定产前诊断策略和具体的干预措施，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.