Master Control Gene Research Articles

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The master control gene for morphogenesis and evolution of the eye.

The human Aniridia, the murine Small eye, and the eyeless mutations of Drosophila affect homologous (Pax-6) genes that contain both a paired- and a homeobox. By ectopic expression of these genes, functional eyes can be induced on the legs, wings, and antennae of the fly, indicating that eyeless (Pax-6) is the master control gene for eye morphogenesis. The finding of Pax-6 from flatworms to humans suggests that eyeless is a universal master control gene and that the various types of eyes in the various animal phyla may have evolved from a single prototype.

Eye ancestry: old genes for new eyes.

The vast differences between vertebrate and arthropod eyes suggest that the recently discovered homologous master control genes for eye development had another function before eyes evolved in the early Cambrian.

Embryonic Expression and DNA-Binding Properties of Zebrafish Pax-6

Zebrafish pax-6 (pax[zf-a]) and its murine homologue are structurally and functionally related to the Drosophila paired box gene eyeless, a master control gene for eye development. This report details the zebrafish pax-6 embryonic expression pattern both at the mRNA and protein level. Transcripts are first detected in the presumptive forebrain and hindbrain regions of the neural plate. After formation of the neural keel, Pax-6 protein accumulates within the same two domains. Expression is also observed in the optic vesicles and lens placodes,confirming that the Pax-6 protein is expressed in those areas of the eye where it is assumed to control differentiation. The relative DNA-binding affinity of the zebrafish Pax-6 protein to different categories of Pax recognition sites is shared with the murine homologue.

Induction of Ectopic Eyes by Targeted Expression of the eyeless Gene in Drosophila

The Drosophila gene eyeless (ey) encodes a transcription factor with both a paired domain and a homeodomain. It is homologous to the mouse Small eye (Pax-6) gene and to the Aniridia gene in humans. These genes share extensive sequence identity, the position of three intron splice sites is conserved, and these genes are expressed similarly in the developing nervous system and in the eye during morphogenesis. Loss-of-function mutations in both the insect and in the mammalian genes have been shown to lead to a reduction or absence of eye structures, which suggests that ey functions in eye morphogenesis. By targeted expression of the ey complementary DNA in various imaginal disc primordia of Drosophila, ectopic eye structures were induced on the wings, the legs, and on the antennae. The ectopic eyes appeared morphologically normal and consisted of groups of fully differentiated ommatidia with a complete set of photoreceptor cells. These results support the proposition that ey is the master control gene for eye morphogenesis. Because homologous genes are present in vertebrates, ascidians, insects, cephalopods, and nemerteans, ey may function as a master control gene throughout the metazoa.

OTIS and the communication industry: risks and benefits

Gene expression arrays reveal the potential linkage of altered gene expression with specific adverse effects leading to disease phenotypes. But how closely do microarray data reflect early physiological or pharmacological measures that predict toxic event(s)? To explore this issue, we have undertaken experiments in early mouse embryos exposed to various teratogens during neurulation stages with the aim of correlating large-scale changes in gene expression across the critical period during exposure. This study reports some of the large-scale changes in gene expression that can be detected in the optic rudiment of the developing mouse and rat embryo across the window of development during which the eye is exceedingly sensitive to teratogen-induced micro-/anophthalmia. Microarray analysis was performed on RNA from the headfold or ocular region at the optic vesicle and optic cup stages when the ocular primordium is enriched for Pax-6, a master control gene for eye morphogenesis. Statistical selection of differentially regulated genes and various clustering techniques identified groups of genes in upward or downward trajectories in the normal optic primordium during early eye development in mouse and rat species. We identified 165 genes with significant differential expression during eye development, and a smaller subset of 58 genes that showed a tight correlation between mouse–rat development. Significantly over-represented functional categories included fatty acid metabolism (up-regulated) and glycolysis (down-regulated). From studies such as these that benchmark large-scale gene expression during normal embryonic development, we may be able to identify the panel of biomarkers that best correlate with species differences and the risks for developmental toxicity.

Chromosomal assignment of seven rat homeobox genes to rat chromosomes 3, 4, 7, and 10.

The homeobox genes are a family of developmental master control genes originally identified in the fruit fly Drosophila. In mammals, the Antennapedia-class homeobox genes are most studied and characterized. These homeobox genes encode sequence-specific DNA-binding proteins and function as transcription regulators to specify positional information in development (for review, see McGinnis and Krumlauf 1992). One striking feature of the Antennapedia-class homeobox genes is that their physical organization in the chromosomes is conserved in evolution. In Drosophila, eight Antennapedia-class homeobox genes are arranged in two clusters, the Antennapedia complex (ANT-C) and the Bithorax complex (BX-C), on Chromosome (Chr) 3. In mice and human, 38 Antennapedia-class homeobox genes have been identified; they are organized in four gene clusters (McGinnis and Krumlauf 1992; Scott 1992). DNA sequence comparisons of the mammalian Antennapedia-class homeobox genes suggest that the four mammalian homeobox gene clusters may have arisen through chromosomal duplications of an ancestral homeobox gene complex (HOM-C) in evolution (Schughart et al. 1989). In both fly and mice, the expression of the Antennapedia-class homeobox genes is in a spatially restricted fashion. Moreover, the physical orders of the homeobox genes in a chromosome are colinear with the spatial domains of expression along the anteroposterior body axis of the embryos (McGinnis and Krumlauf 1992). This conservation of gene order in chromosome and spatial pattern of expression may have important implications in the evolution and function of the homeobox genes. In this report, we describe the chromosomal assignment of seven Antennapedia-class rat homeobox

The homeobox in perspective.

The discovery of the homeobox marks the beginning of a new era in developmental biology in which a class of master control genes, which determine the body plan, have been identified. Their mechanism of action can now be studied at the molecular level and their occurrence seems to be much more universal than originally anticipated.

Clusters of Master Control Genes Regulate the Development of Higher Organisms

Clusters of Master Control Genes Regulate the Development of Higher Organisms

The 1991 Albert Lasker Medical Awards. Clusters of master control genes regulate the development of higher organisms

The 1991 Albert Lasker Medical Awards. Clusters of master control genes regulate the development of higher organisms

X:A ratio, the primary sex-determining signal in Drosophila, is transduced by helix-loop-helix proteins

Drosophila determines its sex by “counting” X chromosomes. We show that premature expression of the pair-rule segmentation gene hairy interferes with this process, resulting in female-specific lethality by inhibiting initiation of the master control gene Sexlethal ( Sxl). The female-specific lethality can be suppressed by a constitutive Sxl allele or by extra copies of X-linked “counting elements.” These results are best explained by competition between hairy and other helix-loop-helix transcription factors that act in chromosome counting. We have confirmed this model by showing that misexpression of the achaete-scute T4 gene induces ectopic Sxl expression and male-specific lethality, confirming that achaete-scute T4 is the sisterless-b counting element. We propose that X chromosomes are counted through heterodimers of helix-loop-helix transcription factors that act synergistically to initiate Sxl expression.

Genes and the Genesis of the CNS: Hints from the Homeobox

At least a third of the human genome is estimated to be devoted to the development and maintenance of the central nervous system (CNS). Recent advances in our understanding of the genetic programming of CNS development are based on the identification of master control genes that are essential for the earliest stages of neurogenesis and the subsequent specification of cell lineages. One class of control genes thought to be involved in CNS development are called "homeobox genes." First discovered in Drosophila (fruit flies), and now recognized in many species including humans, these highly conserved genes code for DNA binding proteins that regulate the expression of other subordinate genes. Although the relevance of homeobox genes to developmental psychopathology and pediatric psychopharmacology may appear remote, interactions between these basic genetic mechanisms and their increasingly complex environments (both macro- and micro-) undoubtedly play a critical role in the initial organization of the CNS and may contribute to the etiology of various developmental disorders.

Introduction

ABSTRACT The current dogma describing the genetic control of development assumes a hierarchy of regulatory genes. In the simplest case, a master control gene directly regulates secondary genes which, in turn, regulate the expression of other genes. In principle the master control genes can be recognized by the pleiotrophic effects caused by mutation, however, complex phenotypic changes are also associated with mutations in many nonregulatory genes. The best-described examples of control genes are from relatively simple organisms with well-developed genetics, for example Drosophila and Caenorhabditis. Unfortunately, identification of developmental control genes in mammals has proved to be difficult, presumably because homeotic and similar mutations are lethal. There is, however, one well-defined developmental control gene in mammals: TDF or the testisdetermining gene (the same locus is called Tdy in mouse). Molecular cloning of TDF will not only facilitate exploration of the fundamental questions of sex determination, but should also provide a model for genetic control of development.

Regulation of the Genes of the Bithorax Complex in Drosophila

The BX-C is a set of master control genes that trans-regulate other genes and thereby control much of the segmentation pattern of the fly. The BX-C genes are themselves regulated in cis and trans. Three rules governing cis-regulation of BX-C are applicable over a region extending from Ubx to at least iab-7, a distance of nearly 300 kb on the DNA map: The colinearity (COL) rule: genes are colinear with respect to map location and order of expression along the body axis, the only exception thus far being pbx+; the cis-inactivation (CIN) rule: a mutant lesion in one gene tends to cis-inactivate the wild-type gene(s) immediately distally; and the cis-overexpression (COE) rule: certain mutant lesions in a given gene cause the next most proximal gene to overexpress one segment more anterior to the one in which the latter gene normally expresses. A model is proposed that attempts to account for these rules by invoking a special cis-regulatory entity (E) that diffuses more efficiently along the chromosome than between chromosomes.