Epithelial bending in mammalian morphogenesis

基因驱动和控制人体组织和器官的胚胎发育，就像软件驱动计算机一样。我们开始理解写在基因组中的“基因程序”。然而，我们对软件如何驱动硬件知之甚少：基因如何驱动我们所看到的物理形状？如果我们希望有一天用生物方法修复硬件，这个问题需要得到回答。为了回答这个问题，我们需要将极其复杂和精细的身体构造过程（称为“形态发生”）分解成更容易分析的子过程。其中之一是弯曲细胞片以形成凹槽或凹坑。这被称为“内陷”。内陷在医学上很重要，因为它发生在大脑和脊髓的形成过程中，它的失败是一种主要的出生缺陷（包括脊柱裂）。我们建议看一些更简单的东西，但这将给出几种不同类型的内陷的答案。我们将检查小鼠牙齿、唾液腺、毛囊和乳腺导管（“外胚层器官”）的形成。每一个器官都是从内陷开始逐渐变深的。我们将使用一些新技术，比以往任何时候都更精确地检测构成内陷片的细胞轮廓，这样我们就可以对它们的结构进行良好的、工程式的测量。最后，我们可以在培养皿中培养这些组织，看看哪种化学“抑制剂”（会干扰细胞中某些已知的蛋白质）会阻止哪一部分的形态发生。这将把细胞运动和形状变化与特定的蛋白质联系起来。由于蛋白质来自已知的基因，这些研究，以及突变研究。将把细胞的形状和运动与基因联系起来，并能够将它们与写在DNA中的遗传软件相匹配。比较这种类型的多个小器官，我们可以了解使它们相似但不同的规则。最终，这种知识将使使用化学信号（软件）驱动结构修复（硬件）成为可能。

Genes drive and control the embryonic development of tissues and organs of the body in the way that software drives a computer. We are beginning to understand "gene programmes" written in the genome. However, we know much less about how the software drives the hardware: how do genes drive the physical shapes that we see? This question needs to be answered if we want one day to fix the hardware using biological methods. To answer this question, the extremely complicated and elaborate process of physical construction of the body (known as "morphogenesis") needs to be broken down into more easily analysed sub-processes. One of these is the bending of a sheet of cells to make a groove or pit. This is called "invagination". Invagination is medically important because it occurs in making the brain and spinal cord and its failure is a major class of birth defects (which includes, for example, spina bifida). We propose to look at something simpler but that will give answers about several different kinds of invagination. We will examine the formation of teeth, salivary glands, hair follicles and mammary ducts ("ectodermal organs") in mice. Each of these organs begins with an invagination that becomes gradually deeper. We will use some new techniques to detect more precisely than ever before the outlines of cells that make up the invaginating sheet so that we can get good, engineering-style measurements of their structures. Finally, we can grow these tissues in a dish and see which kinds of chemical "inhibitors" (which interfere with certain known proteins in the cell) will block which parts of the morphogenesis. This will link the cell movements and shape changes to particular proteins. Since proteins come from known genes, these studies, together with the mutant studies. will link cell shapes and movements to genes and be able to fit them in with the genetic software written in the DNA. comparing multiple small organs of this type, we can get an idea of the rules that make them similar but different. Ultimately this kind of knowledge should make it possible to use chemical signals (software) to drive structural repairs (hardware).