Perspectives Anecdotal , Historical and Critical Commentaries on Genetics The Complex Tale of the achaete – scute Complex : A Paradigmatic Case in the Analysis of Gene Organization and Function During Development-猫眼课题宝

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2009

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A. Garcı́a-Bellido;J. Celis

achaete - scail基因复合体（AS-C）包含4个基因，分别编码bHLH家族转录因子，achaete、scail、lethal of scail和asense，位于含有多个顺式调控位置特异性增强子的40 kb DNA中。这些基因在表皮细胞向神经命运的承诺中发挥关键作用，促进成人周围神经系统感觉器官（刷毛）和胚胎中枢神经系统神经母细胞的形成。对as - c的分析最初集中在achaete （ac）和sccute （sc）等位基因对果蝇成体表皮大毛毛模式影响的位置特异性变化上，并从那里发展成为理解模式形成和细胞承诺的分子基础的关键切入点。从这个角度来看，我们描述了AS-C的研究如何有助于理解真核生物基因组织和解剖模式形成的发育机制。模式的形成包括在发育中的组织或有机体中不断分布的细胞类型。对模式形成的因果机制的分析对发育遗传学产生了重大影响，部分原因是发现了影响果蝇胸部和头部特定空间位置感觉器官形成的遗传变异。特别是，对无毛鳞片基因复合体的研究提供了大量关于基因组织、基因表达的空间调控、细胞承诺的遗传和细胞机制的信息和概念，以及最近基因进化的发育基础和它们决定的模式。在本展望中，我们总结了一些关键方面的棘刺-鳞片复合体已经作出了重大贡献的发育机制的理解调节模式的形成。我们从遗传学的角度总结了无毛和鳞片等位基因的独特特征，从基因的分子分析中获得的信息，以及使无毛-鳞片复合体的研究成为发育基因及其调控过程分析的典范案例的刚毛模式形成的不同方面。这个故事从果蝇成年表皮中achaete （ac）和sce （sc）突变的位置特异性变化开始，正如我们将看到的，它进一步确定了野生型基因在神经发育中的关键作用。在他们被发现的时候，基因只是遗传因素，其等位变异允许它们映射到染色体上。这些基因的功能性质只能从其突变等位基因的表型推断出来。对于William Bateson来说，在20世纪初，突变的等位基因对应于功能的丧失，但当同一基因中出现非互补的多个等位基因时，这个想法开始被重新考虑。对于酶编码基因，这一概念被理解为基本酶功能的部分失效，例如在眼睛色素形成中。白色基因中的多个等位基因导致不同色调的红色，这更难解释。后来发现它们与载体蛋白功能域的突变有关。这些作者对这项工作做出了同样的贡献。通讯作者：Antonio garczi - a- bellido， Centro de biologya - a Molecular Severo Ochoa, universsidad Autónoma de Madrid, Cantoblanco, Madrid 28049，西班牙。电子邮件：agbellido@cbm.uam.es遗传学182:631-639（2009年7月）显示不同的眼睛色素的不同亲和力。无毛鳞片突变体的等位基因系列违背了H. J. Muller提出的基因功能的定量、线性解释（无定形、次形和超形），以基因测试的结果为基础对突变进行分类（Muller 1932）。因此，所有等位基因都表现出去除绒毛上的小毛纲（当时称为“毛”）和一些大毛纲（当时称为“刚毛”）的特异性。sc等位基因只消除了大毛纲的一个子集，即不受ac突变影响的大毛纲（见图1A）。一些sc等位基因在大毛纲的某些位置上表现为不互补，而其他具有不同模式特异性的sc等位基因在不受这些等位基因影响的位置上表现为互补。受影响的大毛藻在单个等位基因和等位基因组合中的位置遵循拓扑顺序（“序列”），这在胸腔中显然是非线性的，但却是不连续的。穆勒在莫斯科的同事（A. S. Serebrovsky， N. P. Dubinin和A. A. Prokofieva等）将这些数据命名为图1。- (A)上一排从左到右：蝇胸的照片（由J. Modolell提供），以及点零等位基因（ac和sc）、sc双突变体和感官缺陷[Df(1)sc2]的左半胸刚毛表型的表示。下一行：无毛体[Df(1)ysc]和鳞片[Df(1)sc]合成缺失左半胸的刚毛表型，鳞片等位基因sc， sc和sc。注意，缺失sc的表型比in (1)sc弱得多。(B)无梗细胞-鳞片复合体表示，表示编码区T5（无梗细胞）、T4（鳞片）、T3（鳞片致死区）和T1a/ T8（鳞片）（水平箭头）；代表性断点的位置（y, sc, sc， sc和sc；垂直箭头）；从这些断点（ysc, sc, sc；实条）构造的删除；和两个近端缺陷，sc和sc（开放式酒吧）。(C)从左到右，由J. Modolell和S. Campuzano提供的原始照片，与T4放射性探针杂交的翼盘切片，与抗ac抗体染色的整片翼盘或与地高西根新标记的T5探针杂交的翼盘，以及与抗ac抗体染色的高放大背中央前膜团。632 A。garctura - bellido和J. F. de Celis

The achaete–scute gene complex (AS-C) contains four genes encoding transcription factors of the bHLH family, achaete, scute, lethal of scute, and asense located in 40 kb of DNA containing multiple cis-regulatory position-specific enhancers. These genes play a key role in the commitment of epidermal cells toward a neural fate, promoting the formation of both sensory organs in the peripheral nervous system (bristles) of the adult and of neuroblasts in the central nervous system of the embryo. The analysis of the AS-C initially focused on the variations in positional specificity of effects of achaete (ac) and scute (sc) alleles on macrochaete bristle pattern in the Drosophila adult epidermis, and from there it evolved as a key entry point into understanding the molecular bases of pattern formation and cell commitment. In this perspective, we describe how the study of the AS-C has contributed to the understanding of eukaryotic gene organization and the dissection of the developmental mechanisms underlying pattern formation. PATTERN formation consists of the generation of constant distributions of cell types in a developing tissue or organism. The analysis of the causal mechanisms underlying pattern formation has had a major impact in developmental genetics, due in part to the identification of genetic variants affecting the formation of sensory organs at specific spatial positions in the thorax and head of the fruit fly. In particular, the study of the achaete–scute gene complex has provided the bulk of information and concepts about gene organization, the spatial regulation of gene expression, the genetic and cellular mechanisms of cell commitment, and, more recently, the developmental bases of the evolution of both the genes and the patterns they determine. In this Perspectives we summarize some of the key aspects of the achaete–scute complex that have made a significant contribution to the understanding of the developmental mechanisms regulating pattern formation. We summarize the particular characteristics of achaete and scute alleles that made them attractive from the genetic point of view, the information gained by the molecular analysis of the genes, and the different aspects of bristle pattern formation that made the study of the achaete–scute complex a paradigmatic case of the analysis of developmental genes and the process they regulate. GENETIC COMPLEXITY OF scute AND achaete MUTATIONS The story began with the variations in positional specificity of achaete (ac) and scute (sc) mutations in the Drosophila adult epidermis, and, as we shall see, it progressed to identify crucial roles for the wild-type genes in neural development. At the time of their discovery, genes were just hereditary factors whose allelic variants allowed their mapping to chromosomes. The functional nature of these genes could be inferred only from the phenotype of their mutant alleles. For William Bateson, at the beginning of the 20th century, mutant alleles corresponded to the loss of function, but this idea started to be reconsidered when noncomplementing multiple alleles in the same gene appeared. For enzyme coding genes, this notion was understood as partial failures of a basic enzymatic function, e.g., in eye pigment formation. Multiple alleles in the white gene, leading to varied tones of red, were more difficult to explain. It was found later that they were related to mutations in functional domains of a carrier protein These authors contributed equally to this work. Corresponding Author: Antonio Garcı́a-Bellido, Centro de Biologı́a Molecular Severo Ochoa, Universidad Autónoma de Madrid, Cantoblanco, Madrid 28049, Spain. Email: agbellido@cbm.uam.es Genetics 182: 631–639 ( July 2009) displaying distinct affinities for different eye pigments. The allelic series of achaete–scute mutants defied a quantitative, lineal interpretation of the function of the genes in the terms suggested by H. J. Muller (amorphs, hypomorphs, and hypermorphs) to classify mutations on the basis of the results of genetic tests (Muller 1932). Thus ac alleles showed specificity for the removal of microchaetae (‘‘hairs’’ at the time) and some macrochaetae (‘‘bristles’’) of the notum. The sc alleles eliminated only a subset of macrochaetae, those not affected by ac mutations (see Figure 1A). Some sc alleles behaved as noncomplementing in certain macrochaetae positions, but other sc alleles with different pattern specificities would complement for the positions not affected by these individual alleles. The positions of affected macrochaetae in individual alleles and allelic combinations followed a topological order (‘‘seriation’’) that was clearly nonlinear in the thorax, but discontinuous. The colleagues of Muller in Moscow (A. S. Serebrovsky, N. P. Dubinin, and A. A. Prokofieva, et al.) designated these sc Figure 1.—(A) Top row from left to right: photograph of the fly thorax (courtesy of J. Modolell) and representations of the bristle phenotype in the left hemithorax of the point null alleles (ac and sc), the sc double mutant, and the asense deficiency [Df(1)sc2]. Bottom row: representation of the bristle phenotype in the left hemithorax of the synthetic deletions for achaete [Df(1)ysc] and scute [Df(1)sc] and the scute alleles sc, sc, and sc. Note that the deficiency sc has a much weaker phenotype than In(1)sc. (B) Representation of the achaete–scute complex, indicating the coding regions T5 (achaete), T4 (scute), T3 (lethal of scute), and T1a/ T8 (asense) (horizontal arrows); the position of representative breakpoints (y, sc, sc, sc, and sc; vertical arrows); the deletions constructed from these breakpoints (ysc, sc, sc; solid bars); and two proximal deficiencies, sc and sc (open bars). (C) From left to right, original photographs (courtesy of J. Modolell and S. Campuzano) of a wing disc section hybridized with a T4 radioactive probe, whole-mount wing discs stained with anti-Ac antibody or hybridized with a T5 probe labeled with digoxigenin, and high magnification of the dorsocentral proneural cluster stained with anti-Ac antibody. 632 A. Garcı́a-Bellido and J. F. de Celis

Perspectives Anecdotal , Historical and Critical Commentaries on Genetics The Complex Tale of the achaete – scute Complex : A Paradigmatic Case in the Analysis of Gene Organization and Function During Development

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