CONTROL OF CELL DIFFERENTIATION DURING PALATAL FUSION

描述(申请人提供)：面部的发育需要一系列复杂的上皮和间充质之间的相互作用。不同的指导性相互作用导致面部原基的图案化，直接与特定头面部结构的发育和特定细胞的命运有关。二次腭部发育有3个阶段，即生长区期、中线内侧缘上皮的背腹型和腭架的前后型。MEE是背腹型的，一些细胞迁移到口腔或鼻腔表面，而另一些细胞则经历上皮-间充质转分化。MEE的细胞命运是以背腹方向建立的，这些命运的调节受到高度控制。腭架的前后方模式调节着腭部融合的时间，并在空间上表现出融合事件的明显规律。腭架的生长区、背腹和前后方的模式受特定的诱导信号的局部调节。转化生长因子-B3已被证明是一个关键的信号分子，在腭突形成过程中调节MEE的命运，并导致假说：内侧边缘上皮细胞的分化受自分泌和旁分泌机制的控制，这些机制在腭突形成过程中建立生长区、背腹和前后方模式。这一假说将通过三个特定的目标进行检验：1.确定在腭裂形成的生长区阶段调节MEE分化的因素及其与EGF信号通路的关系；2.根据细胞黏附分子和生长因子受体的定义，描述在腭架融合过程中MEE的背腹模式，该模式决定了不同群体MEE的特定命运；3)检测MEE的前后模式，该模式定义了在Smad 2过表达中完成融合的不同潜力。识别腭部融合过程中必不可少的分子机制将导致未来应用于开发产前诊断策略和特定干预措施，以减少人类颅面部出生缺陷的发生率。

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.