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， 特别是会聚延伸，细胞插入每个细胞之间， 另一种是产生更长、更窄的结构， 发育中的重要事件，如原肠胚形成和小管形成。 这些过程的普遍性，以及众多的同源性 最近在果蝇和脊椎动物基因之间发现的， 确保了控制形态发生的基因的发现和分析 模式生物果蝇将具有脊椎动物同源物。 后肠的发育提供了一个很好的进入 收敛扩展的问题，因为这个过程发生在 果蝇胚胎细胞增殖后已经发生， 至少对后肠来说，没有相互作用的复杂因素 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描述了早期 建立肠道原基的转录因子层级。 通过筛选影响后肠发育的突变体， 确定了arc基因，该基因控制着 Malpighian小管，以及控制 后肠 Arc蛋白含有一个PDZ结构域， 与顶膜表面相连。我们将描述Arc 通过更详细地定位它，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 和脊椎动物来看看它们是否在形态发生中扮演着类似的角色。 我们 将进行一个分子表征的toxin，以确定其 表达模式、分子特性和细胞定位 Drm蛋白质。 通过基因筛选，我们将发现更多的 以前未描述的基因在后肠中起作用， 形态发生 我们将描述所有这些基因的表型 更详细地（包括在电子显微镜水平上）。 我们将 使用这些数据来生成一个模型的遗传基础趋同 肠小管的延伸形态发生。 表征 果蝇的arc、circ和其他基因将有助于识别 控制形态发生的脊椎动物基因;这些脊椎动物中的缺陷 同源基因可能导致人类出生缺陷。

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.