Molecular Basis of Tissue Interactions that Regulate Craniofacial Development

描述（由申请人提供）：我们第一个资助周期的目标是研究调节颅面发育的组织相互作用的分子介质。我们关注的是大脑在建立一个信号中心——额鼻外胚层区（FEZ）中所起的作用，因为额鼻外胚层区调节上颌的生长模式。我们的研究表明，大脑控制着自由经济区的空间组织，从而产生独特的面部形态，包括沿着连续的形态谱下降的疾病表型。我们的初步数据表明，大脑通过一种新的机制来控制自由经济区的空间组织。这些数据还表明，在面部发育过程中，FEZ是动态的，可以改变表达边界，调节多种形态发生过程。最后，面部发育过程中细胞对Fgf信号的反应在很大程度上是未知的，我们的初步研究表明，基本的细胞过程是由Fgf信号控制的。在FGF信号的作用下，这些细胞行为参与了面部形态发生的调节。总的来说，这些数据提示了用于面部原基发育、整合和融合的机制。基于这些数据，我们假设来自大脑的SHH通过microrna在FEZ中诱导负反馈回路来控制面部形态发生，这有助于确定FEZ中SHH的结构域。然后FEZ协调其自身变化的表达域来控制形态发生过程，如间充质细胞的增殖、迁移和极化，这些细胞驱动形成上颌的面部原基的生长和融合。我们将在三个具体目标中检验这一假设。首先，我们将研究这些微rna在FEZ中调控Shh表达的空间组织的程度，并验证假设的靶基因。其次，自由经济区会随着时间的推移而改变形状，我们将确定Shh的新表达域在鼻中突、鼻外侧突和上颌突的生长和融合过程中所起的作用。第三，我们将研究FGF信号的下游靶点在通过该途径介导细胞对信号的反应中所起的作用，我们将研究Crouzon综合征的小鼠模型。这项研究的结果将导致对控制面部发育的机制的更全面的理解，并将确定与唇腭裂和其他结构性疾病相关的推定疾病引起机制。

DESCRIPTION (provided by applicant): The goal of our first cycle of funding was to examine the molecular mediators of tissue interactions that regulate craniofacial development. We focused on the role that the brain plays in establishing a signaling center, the Frontonasal Ectodermal Zone (FEZ), because the FEZ regulates patterned growth of the upper jaw. Our research revealed that the brain controls the spatial organization of the FEZ, which then produces unique facial morphologies including disease phenotypes that fall along a continuous spectrum of morphologies. Our preliminary data suggest a novel mechanism by which the brain controls the spatial organization of the FEZ. These data also indicate that the FEZ is dynamic and shifts expression boundaries to regulate multiple morphogenetic processes during facial development. Finally, cellular responses to Fgf signaling during facial development have been largely unknown, and our preliminary studies suggest that basic cellular processes are controlled by FGF signaling. In response to FGF signaling these cellular behaviors participate in regulating facial morphogenesis. Collectively, these data suggest mechanisms that are used for development, integration, and fusion of facial primordia. Based on these data, we hypothesize that SHH from the brain controls facial morphogenesis by inducing a negative feedback loop in the FEZ via microRNAs and this helps to define the domain of Shh in the FEZ. The FEZ then orchestrates its own changing expression domain to control morphogenetic processes such as proliferation, migration, and polarization of mesenchymal cells that drive growth and fusion of the facial primordia that form the upper jaw. We will test this hypothesis in three Specific Aims. First, we will examine the extent to which these micro RNAs regulate the spatial organization of Shh expression in the FEZ and validate putative target genes. Second, the FEZ changes shape over time, and we will determine the role that novel expression domains of Shh play during growth and fusion of the median nasal, lateral nasal, and maxillary processes. Third, we will examine the role that downstream targets of FGF signaling have in mediating the cellular response to signaling by this pathway, and we will examine a mouse model of Crouzon Syndrome. The results from this research will lead to a more comprehensive understanding of mechanisms that control facial development and will identify putative disease causing mechanisms related to cleft lip and palate among other structural disease.