The sine oculis homeobox (SIX) protein family is a group of evolutionarily conserved transcription factors that are found in diverse organisms that range from flatworms to humans. These factors are expressed within, and play pivotal developmental roles in, cell populations that give rise to the head, retina, ear, nose, brain, kidney, muscle and gonads. Mutations within the fly and mammalian versions of these genes have adverse consequences on the development of these organs/tissues. Several SIX proteins have been shown to directly influence the cell cycle and are present at elevated levels during tumorigenesis and within several cancers. This review aims to highlight aspects of (1) the evolutionary history of the SIX family; (2) the structural differences and similarities amongst the different SIX proteins; (3) the role that these genes play in retinal development; and (4) the influence that these proteins have on cell proliferation and growth. KeywordsSine oculis; optix; DSix4; Drosophila; SIX; mammals; retina; gonad; mesoderm SIX proteins: A family historyMutations within the founding member of the sine oculis homeobox (SIX) family, sine oculis (so), were first identified and characterized in the fruit fly, Drosophila melanogaster at a time when a growing number of mutants affecting the structure, size and pigmentation of the eye were being recovered [1]. Mutations in so proved to be particularly interesting as loss-offunction mutants not only had dramatic effects on the compound eye but also, in fact, adversely affected the entire visual system [2][3][4][5]. Subsequent molecular efforts identified two additional SIX family members, optix and DSix4 in flies [6,7]. optix, like so, is expressed and functions in the developing eye, although its role in the retina appears to be distinct from that of so [7][8][9]. DSix4, on the other hand, plays no role in the eye but instead functions in several mesoderm derivatives including a subset of somatic muscles, the somatic cells of the gonad and the fat body [10,11]. The three SIX genes that are found in Drosophila are thought to have arisen through the duplication of an ancestral SIX gene, an event that occurred prior to the evolution of the Bilateria. Homologs of the so, optix and DSix4 proteins have been identified in a wide range of organisms throughout the animal kingdom. A comparison of gene structures and sequence has led to the creation of three subclasses of SIX proteins: each class contains one of the fly genes and their orthologs ( Fig. 1) [6]. The remarkable demonstration that Pax6 (ey in flies, Sey in mouse, Pax6 in humans) universally governs retinal development across the animal kingdom was a strong impetus to find vertebrate orthologs of the other genes involved in fly retinal specification [12][13][14]. In the immediate years after cloning so from the fruit fly, homologs were quickly identified in a number of vertebrate systems including medaka fish, chickens, frogs, zebrafish, mice and humans [15][16][17][18][19][20][21][22][23][24][25][26][27][...

Alphaviruses are RNA viruses transmitted between vertebrate hosts by arthropod vectors, primarily mosquitoes. How arthropods counteract alphaviruses or viruses per se is not very well understood. Drosophila melanogaster is a powerful model system for studying innate immunity against bacterial and fungal infections. In this study we report the use of a novel system to analyze replication of Sindbis virus (type species of the alphavirus genus) RNA following expression of a Sindbis virus replicon RNA from the fly genome. We demonstrate deficits in the immune deficiency (Imd) pathway enhance viral replication while mutations in the Toll pathway fail to affect replication. Similar results were observed with intrathoracic injections of whole virus and confirmed in cultured mosquito cells. These findings show that the Imd pathway mediates an antiviral response to Sindbis virus replication. To our knowledge, this is the first demonstration of an antiviral role for the Imd pathway in insects.

The Drosophila compound eye is specified by the concerted action of seven nuclear factors that include Eyeless/Pax6. These factors have been called "master control" proteins because loss-of-function mutants lack eyes and ectopic expression can direct ectopic eye development. However, inactivation of these genes does not cause the presumptive eye to change identity. Surprisingly, we find that several of these eye specification genes are not coexpressed in the same embryonic cells-or even in the presumptive eye. We demonstrate that the EGF Receptor and Notch signaling pathways have homeotic functions that are genetically upstream of the eye specification genes, and show that specification occurs much later than previously thought-not during embryonic development but in the second larval stage.

Summary Since the discovery of a single white eyed male in a population of red eyed flies over 100 years ago (Morgan, 1910), the compound eye of the fruit fly, Drosophila melanogaster, has been a favorite experimental system for identifying genes that regulate various aspects of development. For example, a fair amount of what we know today about enzymatic pathways and vesicular transport is due to the discovery and subsequent characterization of eye color mutants such as white. Likewise, our present day understanding of organogenesis has been aided considerably by studies of mutations, such as eyeless, that either reduce or eliminate the compound eyes. But by far the phenotype that has provided levers into the greatest number of experimental fields has been the humble “rough” eye. The fly eye is comprised of several hundred unit-eyes that are also called ommatidia. These unit eyes are packed into a hexagonal array of remarkable precision. The structure of the eye is so precise that it has been compared to that of a crystal (Ready et al., 1976). Even the slightest perturbations to the structure of the ommatidium can be visually detected by light or electron microscopy. The cause for this is two-fold: (1) any defect that affects the hexagonal geometry of a single ommatidium can and will disrupt the positioning of surrounding unit eyes thereby propagating structural flaws and (2) disruptions in genes that govern the development of even a single cell within an ommatidium will affect all unit eyes. In both cases the effect is the visual magnification of even the smallest imperfection. Studies of rough eye mutants have provided key insights into the areas of cell fate specification, lateral inhibition, signal transduction, transcription factor networks, planar cell polarity, cell proliferation and programmed cell death just to name a few. This review will attempt to summarize the key steps that are required to assemble each ommatidium.

The developing eye of the fruit fly, Drosophila melanogaster, has become a premier model system for studying the genetic and molecular mechanisms that govern tissue determination. Over the last fifteen years a regulatory circuit consisting of the members of the Pax, Six, Eya and Dach gene families has been identified and shown to govern the specification of a wide range of tissues including the retina of both insects and mammals. These genes are not organized in a simple developmental pathway or cascade in which there is a unidirectional flow of information. Rather, there are multiple feedback loops built into the system rendering its appearance and functionality more in line with the workings of a network. In this review I will attempt to describe the genetic, molecular and biochemical interactions that govern the specification of the Drosophila compound eye. In particular, the primary focus will be on the interactions that have been experimentally verified at the molecular and biochemical levels. During the course of this description I will also attempt to place each discovery in its own historical context. While a number of signaling pathways play significant roles in early eye development this review will focus on the network of nuclear factors that promote retinal determination.