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Drosophila melanogaster (fruit fly) is a highly versatile model with a genetic legacy of more than a century. It provides powerful genetic, cellular, biochemical and molecular biology tools to address many questions extending from basic biology to human diseases. One of the most important questions in biology is how a multi-cellular organism develops from a single-celled embryo. The discovery of the genes responsible for pattern formation has helped refine this question and has led to other questions, such as the role of various genetic and cell biological pathways in regulating the process of pattern formation and growth during organogenesis. The Drosophila eye model has been extensively used to study molecular genetic mechanisms involved in patterning and growth. Since the genetic machinery involved in the Drosophila eye is similar to humans, it has been used to model human diseases and homology to eyes in other taxa. This updated second edition covers current progress in the study of molecular genetic mechanisms of pattern formation, mutations in axial patterning, genetic regulation of growth, and more using the Drosophila eye as a model.
Undoubtedly, Drosophila melanogaster, fruit fly, has proved to be one of the most popular invertebrate model organisms, and the work horse for modern day biologists. Drosophila, a highly versatile model with a genetic legacy of more than a century, provides powerful genetic, cellular, biochemical and molecular biology tools to address many questions extending from basic biology to human diseases. One of the most important questions in biology focuses on how does a multi-cellular organism develop from a single-celled embryo. The discovery of the genes responsible for pattern formation has helped refine this question, and led to other questions, such as the role of various genetics and cell biological pathways in regulating the crucial process of pattern formation and growth during organogenesis. Drosophila eye model has been extensively used to study molecular genetic mechanisms involved in patterning and growth. Since the genetic machinery involved in the Drosophila eye is similar to humans, it has been used to model human diseases and homology to eyes in other taxa. This book will discuss molecular genetic mechanisms of pattern formation, mutations in axial patterning, Genetic regulation of growth in Drosophila eye, and more. There have been no titles in the past ten years covering this topic, thus an update is urgently needed.
Complex network of genetic and molecular mechanisms governing the process of organogenesis have an important bearing on development of organisms. We are using an established model of Drosophila melanogaster commonly referred to as fruit fly in order to understand these mechanisms. We have used Drosophila eye to discern genetic hierarchy controlling the (i) event of axial patterning, and (ii) to study neurodegeneration in the developing eye. Axial patterning involves generation of dorsal-ventral (DV), anterior-posterior (AP) and proximal-distal (PD) axes in the organ primordium and is considered crucial for transformation of monolayer epithelium into a three dimensional organ. Any abnormalities in expression patterns of axial patterning genes may result in complete loss of organ. Drosophila eye develops from a default ventral state conferred by expression of genes Lobe (L) and Serrate (Ser). It has been found that antagonistic interaction of dorsal and ventral genes helps generation of midline or the equator which is essential for growth and differentiation of the eye field. Loss-of-function of L/Ser results in complete or loss-of-ventral eye depending on time axis involved. In a genetic modifier screen performed for search for modifiers of L mutant phenotypes, an E3 ubiquitin ligase, Cullin-4 (Cul-4) and GATA-1 transcription factor Pannier (Pnr) were identified. In the current study, we have characterized Cul-4, in promoting cell survival in the ventral domain of developing eye via downregulation of Wingless (Wg) signaling. Cul-4 also regulates JNK signaling to prevent cell death in the developing eye. We thus place the Cul-4 in the hierarchy of ventral genes involved in eye development.We also present the role of GATA-1 transcription factor Pnr in defining the dorsal eye margin boundary by suppressing the eye fate. Pnr downregulates retinal determination gene machinery via zinc finger transcription factor teashirt (tsh). We thus provide a novel mechanism involved in defining dorsal margins of the eye during early stages of organogenesis and an eye suppression function, as a late role of pnr in the developing eye. Identification and characterization of these genes in the dorsal and ventral domains of the eye may help enrich our understanding of the genetic hierarchy and the complex interactions of genes involved in axial patterning in the eye during organogenesis. Since the genetic machinery is highly conserved from flies to humans, these studies will have direct implications on higher vertebrates as well. Other than patterning and growth studies, Drosophila eye has been widely used to study genetic and molecular basis of neurodegeneration. A part of current study is to test the mechanisms involved in the neuronal cell death caused during the course of Alzheimer's disease (AD). AD is caused due to accumulation of Aß-42 peptide which is a product formed because of incorrect cleavage of Amyloid Precursor Protein (APP). Accumulation of Aß-42 results in formation of amyloid plaques which eventually results into stress and the neuronal cell death. We have found that JNK signaling pathway is induced upon Aß-42 accumulation and causes cell death of the neurons in the brain. Our study provides a new mechanistic insight from the perspective of identifying the new targets of AD neuropathy.
1 Kevin Moses It is now 25 years since the study of the development of the compound eye in Drosophila really began with a classic paper (Ready et al. 1976). In 1864, August Weismann published a monograph on the development of Diptera and included some beautiful drawings of the developing imaginal discs (Weismann 1864). One of these is the first description of the third instar eye disc in which Weismann drew a vertical line separating a posterior domain that included a regular pattern of clustered cells from an anterior domain without such a pattern. Weismann suggested that these clusters were the precursors of the adult ommatidia and that the line marks the anterior edge of the eye. In his first suggestion he was absolutely correct - in his second he was wrong. The vertical line shown was not the anterior edge of the eye, but the anterior edge of a moving wave of patterning and cell type specification that 112 years later (1976) Ready, Hansen and Benzer would name the "morphogenetic furrow". While it is too late to hear from August Weismann, it is a particular pleasure to be able to include a chapter in this Volume from the first author of that 1976 paper: Don Ready! These past 25 years have seen an astonishing explosion in the study of the fly eye (see Fig.
An important question in developmental biology is how any three-dimensional organ develops from single monolayer sheet of cells. In multicellular organisms, organogenesis requires axial patterning to determine Antero-Posterior (AP), Dorso-Ventral (DV), and Proximo-Distal (PD) axes. DV patterning marks first lineage restriction event during eye development, any deviation during this event during development results in defective organ formation. We have used Drosophila melanogaster (a.k.a, fruit fly) eye as our model organ as 75% of genetic machinery is conserved between fruit flies and humans and have identified defective proventriculus (dve, a Homeobox gene), an ortholog of SATB-homeobox-1 (special AT-rich sequence binding protein-1 in humans), as a new member of DV- patterning genes hierarchy. We have shown that (1) dve acts downstream of pannier (pnr, a GATA-1 transcription factor), and upstream of wingless (wg), (2) Loss-of-function (LOF) of both dve or pnr results in dorsal eye enlargements, while their Gain-of-function (GOF) suppresses the eye fate, and (3) Furthermore, Wingless (Wg, WNT homolog), downstream target of evolutionarily conserved Hippo growth regulatory pathway, acts downstream of dve in the eye, and exhibits similar eye enlargement or suppression phenotypes upon LOF or GOF. It suggests that like wg, dve also plays an important role in regulating growth. To characterize the function of dve (member of DV patterning pathway) during development, we looked for its interacting partners and found that it interacts antagonistically with Hippo signaling to regulate optimum levels of expression of their common downstream target, Wg, to specify eye versus head fate, during growth and patterning in developing eye. Additionally, GOF of SATB1 (vertebrate ortholog of dve) in the eye also resulted in Wg upregulation and eye suppression. Since GOF of hippo (hpo) triggers cell death, we tested if by blocking cell death by using p35 (anti-apoptotic) exhibits similar phenotypes. We found that eye enlargement phenotype resulting from GOF of hpo in dve domain, is not due to hpo mediated cell death, but by regulating retinal differentiation. Overall, this study presents a model that shows genetic interaction between two unrelated pathways of growth regulation and axial (DV) patterning and have significant bearing on developmental mechanisms. Another focus of this study is to employ Drosophila eye model to study Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disorder characterized by loss of upper and lower motor neurons in central nervous system with no known cure to-date. Mutations in genes like human-Fused in Sarcoma (h-FUS) or cabeza (caz) in Drosophila, have been known to cause ALS in flies. Misexpression of h-FUS-WT (Wild-Type), or FUS mutants FUS-R518K or FUS-R521C in Drosophila eye using GAL4-UAS genetic tool, triggers ALS-mediated neurodegeneration. To understand the mechanism of action, we screened for genetic modifiers and found hippo (hpo), as a genetic modifier. We next tested if this neuroprotective function is exclusive to hpo gene or is dependent on Hippo pathway. We modulated Hippo pathway in FUS-WT or mutant-FUS background and found that downregulation of Hippo pathway, exhibited significant rescue in the eye, but the exact mechanism of action was still unclear. Hippo pathway has been known to activate c-Jun-N-Terminal Kinase (JNK), which is involved in neurodegeneration and cell death. To elucidate the mechanism of action, we modulated JNK signaling in FUS or mutant-FUS background and found that downregulation of JNK signaling also rescued FUS mediated neurodegeneration in eye. This study presents a new model that explains how FUS causes neurodegeneration and has significant bearing on search for future therapeutic targets that can modify neurodegenerative behavior of ALS.
Patterning plays a crucial role during organogenesis. Axial patterning transforms a single sheet of organ primordial cells to a three dimensional organ by defining the Dorsal-Ventral (DV), Anterior-Posterior (AP) and Proximal-Distal (PD) axis. In the Drosophila eye, DV patterning is the first lineage restriction event, which results in formation of the dorsal and ventral compartments of the eye. Loss-of-function (LOF) of genes involved in DV patterning results in loss of the developing eye field. Understanding the mechanism of this crucial process is far from complete, as there is a need to identify more genetic components of this pathway. We have identified defective proventriculus (dve) as a new member of the DV patterning gene hierarchy using the Drosophila eye model. We have shown that dve is expressed in the dorsal domain of the developing eye imaginal disc and induces a downstream target gene wingless (wg), to promote head specific fate and thereby define the boundary between the eye and the head vertex region. Loss of Wg signaling, within the domain of dve expression results in ectopic eye formation. Ectopic eyes seen in the region that forms the head cuticle and antenna of the adult fly (where dve is not expressed) explains the non-autonomous eyes and dorsal eye enlargements seen by blocking dve mediated regulation of Wg. We propose that the ectopic eyes observed in the dve loss-of-function phenotype is due to downregulation of the highly conserved Wg signaling pathway. Interestingly, change of cell fates also involves the role of highly conserved signaling pathways like Wg, Decapentaplegic (Dpp) and Hedgehog (Hh). We will investigate, if dve can regulate morphogen gradients of these signaling molecules to allocate a fate within the developing eye, head and antennal field. Genetic epistasis shows that dve acts downstream of pannier (pnr) to regulate Wg expression in the dorsal eye.We have characterized the novel role of a K50 homeodomain transcription factor, Dve, in regulating Wg expression in the developing eye. dve has a human ortholog, SATB1 (special AT rich sequence binding protein). We found that Dve expressing cells are the sites for expression of Wg in the dorsal head vertex region of eye imaginal disc. Furthermore, we found that dve is involved in generating the Wg gradient in the eye to determine eye versus head fate. This mechanism may also be conserved in other insects like Lucilia sericata and Phormina regina that display sexual dimorphic traits and differential expression of dve may contribute towards this trait. During development, gene regulation occurs by complex transcriptional networks that drive cell-specific patterns of gene expression. At a molecular level, transcriptional programs are orchestrated by the recruitment of transcription factors (TFs) to enhancer elements or cis-regulatory modules (CRMs) that act as modular units, giving rise to a specific spatial-temporal output of gene expression. Using the enhancer library, a valuable tool to identify enhancers we have been able to identify two eye specific enhancers and one wing specific enhancer of dve. We would further use these tissue-specific enhancer lines of dve to identify the TF binding sites that regulate dve expression. Our studies have provided insights into the molecular genetic mechanism by which dve regulates delineation of an eye versus head fate during development and assigned it to the dorsal eye gene hierarchy as a new DV patterning gene.
This book is aimed at generating an updated reservoir of scientific endeavors undertaken to unravel the complicated yet intriguing topic of neurodegeneration. Scientists from Europe, USA and India who are experts in the field of neurodegenerative diseases have contributed to this book. This book will help readers gain insight into the recent knowledge obtained from Drosophila model, in understanding the molecular mechanisms underlying neurodegenerative disorders and also unravel novel scopes for therapeutic interventions. Different methodologies available to create humanized fly models that faithfully reflects the pathogenicities associated with particular disorders have been described here. It also includes information on the exciting area of neural stem cells. A brief discussion on neurofibrillary tangles, precedes the elaborate description of lessons learnt from Drosophila about Alzheimer's, Parkinson’s, Spinomuscular Atrophy, Huntington’s diseases, RNA expansion disorders and Hereditary Spastic Paraplegia. We have concluded the book with the use of Drosophila for identifying pharmacological therapies for neurodegenerative disorders. The wide range of topics covered here will not only be relevant for beginners who are new to the concept of the extensive utility of Drosophila as a model to study human disorders; but will also be an important contribution to the scientific community, with an insight into the paradigm shift in our understanding of neurodegenerative disorders. Completed with informative tables and communicative illustrations this book will keep the readers glued and intrigued. We have comprehensively anthologized the lessons learnt on neurodegeneration from Drosophila and have thus provided an insight into the multidimensional aspects of pathogenicities of majority of the neurodegenerative disorders.