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Regulation Of The Wnt/Wingless Receptor Lrp6/Arrow By The Deubiquitylating Complex Usp46, Zachary T. Spencer

Dartmouth College Ph.D Dissertations

The evolutionarily conserved Wnt/Wingless signal transduction pathway is critical for the proper development of all animals and implicated in numerous diseases in adulthood. Upon binding of the Wnt/Wingless ligand, a cascade of events culminates in inactivation of the destruction complex, a negative regulator of the pathway, and the subsequent formation of singalosomes which mediate pathway activation. A critical component of signalosome formation is the Wnt/Wingless receptor LRP6/Arrow. Upon canonical pathway activation, LRP6/Arrow undergoes activation via phosphorylation by several kinases and complexes with another Wnt/Wingless receptor Frizzled, along with several cytoplasmic components. While many studies have investigated the regulatory mechanisms of …

Mutations In The N-Terminus Of The Mod(Mdg4) Btb Domain Reveal An Unexpected Role Of Mod(Mdg4) In Chromosome Segregation In Female Meiosis, Gwyneth D E Walker, Bruce D. Mckee

Chancellor’s Honors Program Projects

No abstract provided.

The Importance Of Protein Context In Spinocerebellar Ataxia Type 3, Sean Luis Johnson

Wayne State University Dissertations

Spinocerebellar Ataxia Type 3 (SCA3) is a member of the family of polyglutamine (polyQ) neurodegenerative disorders that includes Huntington's Disease and several other SCAs. SCA3, the most common dominant ataxia in the world, is caused by polyQ tract expansion in the protein, ataxin-3. How SCA3 occurs and how to treat it remain unresolved issues. The primary culprit of toxicity in all polyQ diseases is the glutamine repeat: its abnormal expansion leads to neuronal dysfunction and death. With that said, there is indisputable evidence that the way polyQ-dependent toxicity presents—areas impacted, cellular processes perturbed—is predicated in large part on regions outside …

Molecular And Genetic Studies Of Robo2 Transcriptional Regulation In The Central Nervous System Of Drosophila Melanogaster, Muna Abdal Rahim Abdal Rhida

Graduate Theses and Dissertations

Drosophila Robo2 axon guidance receptor is a member of the evolutionarily conserved Roundabout (Robo) protein family that is involved in directing axons that cross the midline to the other side of the animal body. Robo2 roles mainly depend on two factors: The functional domains of the Robo2 protein, which is extensively studied, and the dynamic transcription of robo2 in various subsets of cells throughout embryogenesis which is not fully understood. Thus, knowing robo2 enhancers that transcriptionally regulate robo2 during embryogenesis is significant. To investigate robo2 potential enhancers, we screened 17 transgenic lines of Drosophila that were generated by Janelia Research …

Role Of Rna Helicases In The Drosophila Germline, Patrick Blatt

Legacy Theses & Dissertations (2009 - 2024)

Gametogenesis, the process of creating egg or sperm, is required for launching successive generations of sexually reproducing organisms. The developmental milestones that occur during gamete production have been studied for decades and are of critical interest to gain insight to conserved features of human fertility. Drosophila has been used for over a century as an efficient research model and remains pivotal in uncovering fundamental biological paradigms. During Drosophila egg production, or oogenesis, several developmental transitions must be traversed to ensure completion of oogenesis including: Germline Stem Cell (GSC) maintenance and differentiation, mitotic and meiotic cell divisions, and production of maternally …

Structural Characterization Of The Novel Flightin Domain Wyr And Its Defining Role In The Thick Filament Structure And Mechanics, Lynda Menard

Graduate College Dissertations and Theses

The evolutionary success of Insecta has been attributed largely to the development of efficient means of motility: flight powered by muscle architecture harboring a largely conserved yet tunable system of power relay. The indirect flight muscle (IFM) of Drosophila melanogaster is a well-studied model for dissection of the structural and mechanical means by which muscle operates and evolves. Striated muscle, conserved throughout Animalia, is demarcated by an ordered array of thick- and thin-filaments prominently composed of the proteins myosin and actin. Flightin (fln) is a myosin binding thick filament protein essential for IFM stability, structure and function. The manner by …

The Receptor Basis Of Serotonergic Modulation In An Olfactory Network, Tyler Ryan Sizemore

Graduate Theses, Dissertations, and Problem Reports

Neuromodulation is a nearly ubiquitous process that endows the nervous system with the capacity to alter neural function at every level (synaptic, circuit, network, etc.) without necessarily adding new neurons. Through the actions of neuromodulators, the existing neural circuitry can be adaptively tuned to achieve flexible network output and similarly dynamic behavioral output. However, despite their near ubiquity in all sensory modalities, the mechanisms underlying neuromodulation of sensory processing remain poorly understood. In this dissertation, I address three main questions regarding the mechanisms of one modulator (serotonin) within one sensory modality (olfaction). I begin by establishing a "functional atlas" of …

Launching The Next Generation : Transcriptional Regulation During Oogenesis, Alicia K. Mccarthy

Legacy Theses & Dissertations (2009 - 2024)

Germ cells give rise to gametes and link generations by passing genetic information from parent to offspring. Gametes arise from, in many sexually reproducing organisms, germline stem cells (GSCs) which are set aside early during development. GSCs have an amazing capacity to undergo self-renewal to give rise to a pool of undifferentiated cells, while also differentiating to generate specialized germ cells such as haploid gametes. Upon female GSC differentiation, mitotically dividing germ cells can initiate meiosis, and mature within a follicle. During maturation, the specified oocyte is provided with a trust fund of RNAs and proteins for the next generation …

Role Of The Drosophila Beaf Protein In Chromatin Domain Insulator And Promoter Function, Mukesh Maharjan

LSU Doctoral Dissertations

Proper folding of eukaryotic genomes is required to allow correct interactions between different parts of chromosomes. Precise and timely interactions among different parts of a chromosome allow proper functioning inside a nucleus, including gene regulation, DNA replication and DNA repair. Eukaryotic regulatory elements that facilitate folding and interactions include enhancers, promoters and insulator elements. Insulator elements and their binding proteins play an important role in regulating correct chromatin structure and function. The Drosophila melanogaster special chromatin structure (scs’) is one such insulator. The Boundary Element Associated Factor (BEAF) binds to scs’. BEAF is a 32 kDa protein that has two …

Delineation Of Events In Centripetal Migration During Drosophila Oogenesis, Travis Tait Parsons

UNLV Theses, Dissertations, Professional Papers, and Capstones

All multicellular organisms initially start out as a single cell. This cell must use the genetic information encoded in its DNA to multiply in number and build itself into a complex multicellular organism. How this process occurs is the focus of developmental biology, a field that seeks to understand how a combination of genetic information and environmental conditions shape a cell from its beginnings as a zygote all the way to maturity. A fundamental part of this process is the ability of cells to work together in order to build complex tissues and organs. Cells achieve this coordination by using …

Mechanisms Of Oriented Cell Division And Their Roles In Tissue Development, Evan Blake Dewey

Biology ETDs

Properly executed cell division is crucial to development, maintenance, and longevity of multicellular organisms. Defects in both symmetric and asymmetric divisions can lead to improper developmental patterning, as well as genomic instability, disruption of tissue homeostasis, and cancer. Our research focuses on how regulators orchestrate proper cell divisions. Mushroom Body Defect (Mud) is one such regulator, and here we describe how Mud is regulated via the Hippo signaling pathway kinase Warts (Wts), showing Wts phosphorylates Mud to enhance interaction with the polarity protein Partner of Inscuteable, promoting spindle orientation activity. We next focus on another regulator, Shortstop (Shot), describing a …

The Drosophila Neuroblasts: A Model System For Human Ribosomopathies, Sonu Shrestha Baral

LSU Doctoral Dissertations

This dissertation describes the use of Drosophila neuroblasts (NBs) to model human ribosomopathies; the overall goal is to understand why specific stem cell and progenitor cell populations are the primary targets in nucleolar stress as seen in the ribosomopathies. Chapter 1 provides an overview of relevant literature. Chapter 2 describes nucleolar stress in Drosophila neuroblasts as a model for human ribosomopathies. For this, we induce nucleolar stress by using the UAS-GAL4 system to express RNAi that depletes Nopp140 transcripts, and we also employ homozygous, CRISPR-Cas9-generated Nopp140 gene disruptions with a systemic null phenotype (Nopp140-/-). Embryonic lethality was observed …

Investigation For Novel Anti-Apoptotic Factors In The Neurons Of Drosophila Melanogaster, Haylie Rachel Lam

Chancellor’s Honors Program Projects

No abstract provided.

Regulated Transcriptional Silencing Promotes Germline Stem Cell Differentiation In Drosophila Melanogaster, Pooja Flora

Legacy Theses & Dissertations (2009 - 2024)

Germ cells are the only cell in an organism that have the capacity to give rise to a new organism and are passed from one generation to the next. Therefore, to maintain this unique ability of totipotency and immortality, germ cells execute specific functions, such as, repression of a somatic program and contour a germ line-specific pre- and post-transcriptional gene regulatory landscape. In many sexually reproducing organisms, germ cells are formed during the earliest stages of embryogenesis and undergoes several stages of development to eventually get encapsulated by the somatic cells of the gonad. Once, in the gonad, the germ …

Chromatin-Signaling Axis Orchestrates The Formation Of Germline Stem Cell Differentiation Niche In Drosophila, Maitreyi Upadhyay

Legacy Theses & Dissertations (2009 - 2024)

Stem cells have the unique capability of self-renewing into stem cells and differentiating into several terminal cell types. Loss of either of these processes can lead to aging, progression towards degenerative diseases and cancers. Insight into how self-renewal and differentiation are regulated will have tremendous therapeutic impact. Drosophila is an excellent model system for stem cell study due to the availability of various mutants, markers and RNAi technology. In order to study stem cell biology, we use female Drosophila gonads, whose stem cell population – the germline stem cells (GSCs) gives rise to gametes.

Studies Of Norspermidine Uptake In Drosophila Suggest The Existence Of Multiple Polyamine Transport Pathways, Michael Dieffenbach

Honors Undergraduate Theses

Polyamines are a class of essential nutrients involved in many basic cellular processes such as gene expression, cell proliferation, and apoptosis. Without polyamines, cell growth is delayed or halted. Cancerous cells require an abundance of polyamines through a combination of synthesis and transport from the extracellular environment. An FDA-approved drug, D,L-α-difluoromethylornithine (DFMO), blocks polyamine synthesis but is ineffective at inhibiting cell growth due to polyamine transport. Thus, there is a need to develop drugs that inhibit polyamine transport to use in combination with DFMO. Surprisingly, little is known about the polyamine transport system in humans and other eukaryotes. Understanding the …

A Combined Computational Strategy Of Sequence And Structural Analysis Predicts The Existence Of A Functional Eicosanoid Pathway In Drosophila Melanogaster, Michael Scarpati

Dissertations, Theses, and Capstone Projects

With increased understanding of their roles in signal transduction and metabolism, eicosanoids have emerged as important players in human health and disease. Mammalian prostanoids and related lipid mediators perform varied functions in different tissues and organs. Synthesized through the oxygenation of C20 polyunsaturated fatty acids, mammalian eicosanoids are both pro- and anti-inflammatory. The physiological contexts in which eicosanoid family members act at the cellular level are not well understood. In this study, we examined whether the genome of Drosophila melanogaster, a powerful model for innate immunity and inflammation, codes for the enzymes required for eicosanoid biosynthesis. We report the …

A Genetic Analysis Of Nuclear Functions Of The Lipin Protein In Drosophila Melanogaster, Xeniya Rudolf

Graduate Theses and Dissertations

Lipins are a family of proteins that have critical functions in the control of fat storage and energy homeostasis. Biochemically, lipins have two functions. They provide an enzymatic activity (phosphatidate phosphatase or PAP activity) in the glycerol-3 phosphate pathway that leads to the production of storage fats (triacylglycerols). In addition, they play a role in the regulation of genes in the cell nucleus as transcriptional co-regulators. The PAP activity of lipins has been widely studied in a number of organisms. However, the transcriptional co-regulator function is not as well described in the literature. The transcriptional function of lipins depends on …

Functional Significance Of Branch Points In Mirtrons, Britton A. Strickland

Honors Theses

MicroRNAs are a heterogeneous group of small regulatory RNAs generated by many pathways. Mirtrons (miR) are a class of microRNAs produced by splicing, and some mirtrons contain a 3’ tail located downstream from the self-complementary hairpin. During RNA splicing, a loop-like “lariat” intermediate structure is created when the 5’ end of the RNA is attached to an adenine called the branch point. The goal of this project is to uncover the contribution of branch point location to the processing of tailed mirtrons into functional gene regulators. This project approaches this issue from two directions. First, branch points were identified by …

Characterization Of Vesicular Monoamine Transporter 2 And Its Role In Parkinson's Disease Pathogenesis Using Drosophila, Antonio Joel Tito Jr., Sheng Zhang

Dissertations & Theses (Open Access)

Parkinson’s disease (PD) is a progressive neurodegenerative disorder caused by the selective loss of the dopaminergic neurons in the Substantia nigra pars compacta region of the brain. PD is also the most common neurodegenerative disorder and the second most common movement disorder. PD patients exhibit the cardinal symptoms, including tremor of the extremities, rigidity, slowness of movement, and postural instability, after 70-80% of DA neurons degenerate. It is, therefore, imperative to elucidate the underlying mechanisms involved in the selective degeneration of DA neurons. Although increasing numbers of PD genes have been identified, why these largely widely expressed genes induce …

Axonal Transport And Life Cycle Of Mitochondria In Parkinson's Disease Model, Hyun Sung

Open Access Dissertations

In neurons, normal distribution and selective removal of mitochondria are essential for preserving compartmentalized cellular function. Parkin, an E3 ubiquitin ligase associated with familial Parkinson’s disease, has been implicated in mitochondrial dynamics and removal. However, it is not clear how Parkin plays a role in mitochondrial turnover in vivo, and whether the mature neurons possess a compartmentalized Parkin-dependent mitochondrial life cycle. Using the live Drosophila nervous system, here, I investigate the involvement of Parkin in mitochondrial dynamics; organelle distribution, morphology and removal. Parkin deficient animals displayed less number of axonal mitochondria without disturbing organelle motility behaviors, morphology and metabolic state. …

An Analysis Of The Interaction Between Sin3 And Methionine Metabolism In Drosophila, Mengying Liu

Wayne State University Dissertations

Chromatin modification and cellular metabolism are tightly connected. The mechanism for this cross-talk, however, remains incompletely understood. SIN3 controls histone acetylation through association with the histone deacetylase RPD3. In this study, my major goal is to explore the mechanism of how SIN3 regulates cellular metabolism.

Methionine metabolism generates the major methyl donor S-adenosylmethionine (SAM) for histone methylation. In collaboration with others, I report that reduced levels of some enzymes involved in methionine metabolism and histone demethylases lead to lethality, as well as wing development and cell proliferation defects in Drosophila melanogaster. Additionally, disruption of methionine metabolism can directly affect histone …

A Novel Role For Repetitive Sequences In Recognition Of The Drosophila Melanogaster X Chromosome, Sonal Suresh Joshi

Wayne State University Dissertations

In humans and fruit flies, males have one X chromosome while females have two. This imbalance in gene dosage is potentially lethal, and the process of dosage compensation corrects it. The MSL (Male Specific Lethal) complex, which is composed of five proteins and one of two functionally redundant long non-coding roX (RNA on the X) RNAs, brings about dosage compensation in Drosophila melanogaster. In fruit fly dosage compensation, all the genes on the single male X chromosome are upregulated approximately twofold, via chromatin modifications, to equalize gene dosage with the two X chromosomes of females. This process calls for highly …

Investigating Notch Signaling And Sequential Segmentation In The Fairy Shrimp, Thamnocephalus Platyurus, Sara Izzat Khalil

Senior Theses and Projects

Segmentation is a key feature of arthropod diversity and evolution. In the standard model for arthropod development, Drosophila melanogaster, segments develop simultaneously by a progressive subdivision of the embryo. By contrast, most arthropods add segments sequentially from a posterior region called the growth zone and in a manner similar to vertebrates.

Recent work, mainly focused on insects, suggests that Notch signaling might play a role in arthropods that segment sequentially. These studies document a potential regulatory similarity between sequentially segmenting arthropods and vertebrates. In vertebrates, somite formation involves a molecular oscillator that functions as a pacemaker, driving periodic expression …

Analyzing The Interactions Of Kdm5/Lid And Sin3 In Drosophila Melanogaster, Ambikai Gajan

Wayne State University Dissertations

SIN3, the scaffold protein of a histone modifying complex is conserved from yeast to mammals. Drosophila SIN3 associates with both a histone deactylase RPD3 and a histone demethylase dKDM5/LID. Immunopurification of dKDM5/LID verifies a previously observed interaction with SIN3 and RPD3. Furthermore, deficiency of dKDM5/LID phenocopies deficiency of SIN3 in many cellular and developmental processes. Knockdown of both Sin3A and lid hinder cell proliferation in Drosophila cultured cells and developing flies. Knockdown of these genes also results in a curved wing phenotype implicating a role in wing development. Analysis of underlying gene expression changes upon decreased expression of SIN3, dKDM5/LID …

Drosophila Cyclin J And The Somatic Pirna Pathway Cooperate To Regulate Germline Stem Cells, Paul Michael Albosta

Wayne State University Dissertations

Cyclin J (CycJ) is a highly conserved cyclin that is uniquely expressed specifically in ovaries in Drosophila. Deletion of the genomic region containing CycJ and adjacent genes resulted in a genetic interaction with neighboring piRNA pathway gene, armitage (armi). Here I assessed oogenesis in CycJ null in the presence or absence of mutations in armi or other piRNA pathway genes. Although CycJ null flies had decreased egg laying and hatching rates, ovaries appeared normal indicating that CycJ is dispensable for oogenesis under normal conditions. Further double mutant analysis of CycJ and neighbor armi, as well as two other piRNA pathway …

A Protective Role Of Autophagy In A Drosophila Model Of Friedreich's Ataxia (Frda), Luan Wang

Wayne State University Dissertations

Friedreich’s ataxia (FRDA) is an inherited autosomal recessive neurodegenerative disease. It affects 1 in every 50,000 people in central Europe and North America. FRDA is caused by deficiency of Frataxin, an essential mitochondrial iron chaperone protein, and the associated oxidative stress damages. Autophagy, a housekeeping process responsible for the bulk degradation and turnover of long half-life proteins and organelles, is featured by the formation of double-membrane vacuoles and lysosomal degradation. Previous researches indicate that Danon’s disease, the inherited neural disorder disease that shares similar symptoms with FRDA, is due to the malfunction of autophagy. Based on this, we raise the …

Sex And Heterochromatin: An Investigation Of Sexual Dimorphism In Drosophila Melanogaster, Manasi S. Apte

Wayne State University Dissertations

Over 30% of Drosophila genome is assembled into heterochromatin. Heterochromatin is relatively gene poor, transcriptionally less active and remains condensed during interphase. Previous studies established that roX RNA and some of the Male Specific Lethal (MSL) proteins, all components of the dosage compensation complex, are required for full expression of autosomal heterochromatic genes in male flies but not in females. This was surprising since heterochromatin is generally not thought to be sexually dimorphic. The genetic basis for the regulation of sex-specific heterochromatin was completely unknown.

To determine if roX RNAs localize directly at the heterochromatic regions that they regulate, I …

Studies On Solo Working Mechanism In The Meiosis Of Drosophila Melanogaster, Qian Ma

Masters Theses

In eukaryotes, sister chromatids are closely aligned due to cohesion, a process essential for chromosome pairing and segregation during both mitosis and meiosis. A conserved cohesin complex in a ring structure is composed of four subunits, including each of these four members or their homologs, SMC1, SMC3, SCC1/RAD21/REC8, and SCC3/SA. Up to now, no REC8 homolog has been identified in the meiosis of Drosophila. SOLO is a meiotic protein required for accurate chromosome segregation, centromere cohesion, and cohesin complex localization in Drosophila meiosis. In addition, SOLO is required for synapsis and recombination in Drosophila female meiosis.

In this study, …

Studying Aggregate Formation By Amyotrophic Lateral Sclerosis-Associated Mutant Sod1 Protein In Drosophila Model, Michael Mccarthy

Dissertations & Theses (Open Access)

A common pathological hallmark of most neurodegenerative disorders is the presence of protein aggregates in the brain. Understanding the regulation of aggregate formation is thus important for elucidating disease pathogenic mechanisms and finding effective preventive avenues and cures. Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a selective neurodegenerative disorder predominantly affecting motor neurons. The majority of ALS cases are sporadic, however, mutations in superoxide dismutase 1 (SOD1) are responsible for about 20% of familial ALS (fALS). Mutated SOD1 proteins are prone to misfold and form protein aggregates, thus representing a good candidate for studying aggregate formation. …