GENES CONTROLLING GUT MORPHOGENESIS

我们现在能够研究分子/遗传 控制形态发生的途径。某些形态发生的过程， 尤其是会聚延伸，其中细胞嵌入在每个 其他生成更长、更窄的结构对许多人来说都是常见的 发育中的关键事件，如原肠形成和小管发生。 这些过程的一般性，以及许多同源 最近在果蝇和脊椎动物之间发现的基因，实际上 确保控制形态发生的基因在 模式生物果蝇将会有脊椎动物的同源物。 后肠的发育提供了进入 收敛扩展问题，因为这个过程发生在 果蝇胚胎在细胞增殖后已经发生，并在 至少对于后肠来说，没有复杂的相互作用因素 有中胚层。此外，我们和其他人的早期工作 胚胎模式的实验室已经将早期的 建立肠道原基的转录因子层次结构。 通过筛选影响后肠发育的突变，我们已经 发现了控制细胞内收敛延伸的Arc基因 和DRM基因，它控制着肾小管的伸长 后肠。Arc蛋白包含一个单独的PDZ结构域，似乎 与根尖膜面相关联。我们将描述Arc的特征 通过更详细地定位它来发挥作用，并确定哪些蛋白质 它与之相互作用。我们将在果蝇中寻找Arc相关蛋白 以及脊椎动物，看看它们在形态发育中是否扮演类似的角色。我们 将对DRM进行分子表征，以确定其 表达模式，以及分子特性和细胞定位 DRM蛋白。使用基因筛查，我们将识别出其他 在后肠起作用的以前未被描述的基因 形态发生。我们将描述所有这些基因的表型。 更详细的(包括在电子显微镜层面)。我们会 使用这些数据来生成收敛的遗传基础的模型 肠小管的伸展形态发生。刻画人物形象 果蝇Arc、DRM和其他基因将有助于识别 控制形态发生的脊椎动物基因；这些脊椎动物的缺陷 同源词可能会导致人类的出生缺陷。

We are now in the position to be able to study molecular/genetic pathways controlling morphogenesis. Certain processes of morphogenesis, particularly convergent extension, which cells intercalate between each other to generate a longer, narrower structure, are common to many crucial events in development, such as gastrulation and tubulogenesis. The generality of these processes, as well as the numerous homologies recently discovered between Drosophila and vertebrate genes, virtually assures that genes controlling morphogenesis discovered and analyzed in the model organism Drosophila will have vertebrate homologs. Development of the posterior gut provides an excellent entree into the problem of convergent extension, since this process occurs in the Drosophila embryo after cell proliferation has already occurred, and at least for the hindgut, without the complicating factor of interaction with mesoderm. Additionally, earlier work from our and other laboratories on embryonic patterning has already characterized the early transcription factor hierarchy that establishes the gut primordia. By screening for mutants affecting posterior gut development, we have identified the arc gene, which controls convergent extension in the Malpighian tubules, and the drm gene, which controls elongation of the hindgut. The Arc protein contains a single PDZ domain and appears to associate with the apical membrane surface. We will characterize Arc function by localizing it in more detail, and determining what proteins it interacts with. We will look for Arc-related proteins in Drosophila and vertebrates to see if they play similar roles in morphogesis. We will carry out a molecular characterization of drm, to determine its expression pattern, and the molecular properties and cellular location of the Drm protein. Using genetic screens, we will identify additional previously undescribed genes that play a role in posterior gut morphogenesis. We will characterize phenotypes of all of these genes in more detail (including at the electron microscope level). We will use these data to generate a model for the genetic basis of convergent extension morphogenesis in gut tubules. Characterization of the Drosophila arc, drm and other genes will assist in identifying vertebrate genes controlling morphogenesis; defects in these vertebrate cognates are likely to contribute to human birth defects.