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Trends in Biochemical Sciences Dec 2023The ability of neurites of the same neuron to avoid each other (self-avoidance) is a conserved feature in both invertebrates and vertebrates. The key to self-avoidance... (Review)
Review
The ability of neurites of the same neuron to avoid each other (self-avoidance) is a conserved feature in both invertebrates and vertebrates. The key to self-avoidance is the generation of a unique subset of cell-surface proteins in individual neurons engaging in isoform-specific homophilic interactions that drive neurite repulsion rather than adhesion. Among these cell-surface proteins are fly Dscam1 and vertebrate clustered protocadherins (cPcdhs), as well as the recently characterized shortened Dscam (sDscam) in the Chelicerata. Herein, we review recent advances in our understanding of how cPcdh, Dscam, and sDscam cell-surface recognition codes are expressed and translated into cellular functions essential for neural wiring.
Topics: Animals; Cell Adhesion Molecules; Cell Communication; Drosophila Proteins; Neurons; Protein Isoforms; Invertebrates; Vertebrates; Protocadherins
PubMed: 37839971
DOI: 10.1016/j.tibs.2023.09.001 -
Journal of Biological Rhythms Aug 2023Temperature influences animal physiology and behavior. Animals must set an appropriate body temperature to maintain homeostasis and maximize survival. Mammals set their... (Review)
Review
Temperature influences animal physiology and behavior. Animals must set an appropriate body temperature to maintain homeostasis and maximize survival. Mammals set their body temperatures using metabolic and behavioral strategies. The daily fluctuation in body temperature is called the body temperature rhythm (BTR). For example, human body temperature increases during wakefulness and decreases during sleep. BTR is controlled by the circadian clock, is closely linked with metabolism and sleep, and entrains peripheral clocks located in the liver and lungs. However, the underlying mechanisms of BTR are largely unclear. In contrast to mammals, small ectotherms, such as , control their body temperatures by choosing appropriate environmental temperatures. The preferred temperature of increases during the day and decreases at night; this pattern is referred to as the temperature preference rhythm (TPR). As flies are small ectotherms, their body temperature is close to that of the surrounding environment. Thus, TPR produces BTR, which exhibits a pattern similar to that of human BTR. In this review, we summarize the regulatory mechanisms of TPR, including recent studies that describe neuronal circuits relaying ambient temperature information to dorsal neurons (DNs). The neuropeptide diuretic hormone 31 (DH31) and its receptor (DH31R) regulate TPR, and a mammalian homolog of DH31R, the calcitonin receptor (CALCR), also plays an important role in mouse BTR regulation. In addition, both fly TPR and mammalian BTR are separately regulated from another clock output, locomotor activity rhythms. These findings suggest that the fundamental mechanisms of BTR regulation may be conserved between mammals and flies. Furthermore, we discuss the relationships between TPR and other physiological functions, such as sleep. The dissection of the regulatory mechanisms of TPR could facilitate an understanding of mammalian BTR and the interaction between BTR and sleep regulation.
Topics: Humans; Animals; Mice; Drosophila melanogaster; Temperature; Drosophila Proteins; Circadian Rhythm; Drosophila; Mammals
PubMed: 37222551
DOI: 10.1177/07487304231171624 -
Proceedings of the National Academy of... Jul 2023Autophagy is a major means for the elimination of protein inclusions in neurons in neurodegenerative diseases such as Parkinson's disease (PD). Yet, the mechanism of...
Autophagy is a major means for the elimination of protein inclusions in neurons in neurodegenerative diseases such as Parkinson's disease (PD). Yet, the mechanism of autophagy in the other brain cell type, glia, is less well characterized and remains largely unknown. Here, we present evidence that the PD risk factor, Cyclin-G-associated kinase (GAK)/ homolog Auxilin (dAux), is a component in glial autophagy. The lack of GAK/dAux increases the autophagosome number and size in adult fly glia and mouse microglia, and generally up-regulates levels of components in the initiation and PI3K class III complexes. GAK/dAux interacts with the master initiation regulator UNC-51like autophagy activating kinase 1/Atg1 via its uncoating domain and regulates the trafficking of Atg1 and Atg9 to autophagosomes, hence controlling the onset of glial autophagy. On the other hand, lack of GAK/dAux impairs the autophagic flux and blocks substrate degradation, suggesting that GAK/dAux might play additional roles. Importantly, dAux contributes to PD-like symptoms including dopaminergic neurodegeneration and locomotor function in flies. Our findings identify an autophagy factor in glia; considering the pivotal role of glia under pathological conditions, targeting glial autophagy is potentially a therapeutic strategy for PD.
Topics: Animals; Mice; Drosophila; Auxilins; Autophagy-Related Protein-1 Homolog; Autophagy; Parkinson Disease; Cyclins; Neuroglia; Drosophila Proteins; Autophagy-Related Proteins; Membrane Proteins
PubMed: 37428930
DOI: 10.1073/pnas.2301002120 -
Frontiers in Endocrinology 2023It has been established that encodes E3 ubiquitin ligase, which determines the specificity of substrate binding during protein ubiquitination and has been associated...
INTRODUCTION
It has been established that encodes E3 ubiquitin ligase, which determines the specificity of substrate binding during protein ubiquitination and has been associated with various functions of the nervous system but not the reproductive system. Herein, we explored the role of on fertility with a .
METHODS
Different knockdown flies were established using the UAS/GAL4 activating sequence system. Fertility, hatchability, and testis morphology were studied, and bioinformatics analyses were conducted. Our results indicated that deficiency could induce male sterility and influent egg hatchability in .
RESULTS
We found that deficiency affected the testis during morphological analysis. Proteomics analysis indicated 188 upregulated proteins and 175 downregulated proteins in the testis of knockdown flies. Gene Ontology analysis revealed significant upregulation of and , and downregulation of in knockdown flies. These proteins were involved in the biometabolic or reproductive process in . These regulated proteins are important in testis generation and sperm storage promotion. Bioinformatics analysis verified that was low expressed in cryptorchidism patients, which further supported the important role of in male fertility.
DISCUSSION
Overall, our findings suggest that deficiency could promote male infertility and may be involved in the protein modification of by upregulating and , whereas downregulating Pelota protein expression.
Topics: Humans; Animals; Male; Drosophila; Testis; Drosophila Proteins; Semen; Infertility, Male; Calmodulin-Binding Proteins; Ubiquitin-Protein Ligases
PubMed: 37529615
DOI: 10.3389/fendo.2023.1165825 -
EMBO Reports Dec 2023Planar cell polarity (PCP) signaling polarizes epithelial cells within the plane of an epithelium. Core PCP signaling components adopt asymmetric subcellular...
Planar cell polarity (PCP) signaling polarizes epithelial cells within the plane of an epithelium. Core PCP signaling components adopt asymmetric subcellular localizations within cells to both polarize and coordinate polarity between cells. Achieving subcellular asymmetry requires additional effectors, including some mediating post-translational modifications of core components. Identification of such proteins is challenging due to pleiotropy. We used mass spectrometry-based proximity labeling proteomics to identify such regulators in the Drosophila wing. We identified the catalytic subunit of protein phosphatase1, Pp1-87B, and show that it regulates core protein polarization. Pp1-87B interacts with the core protein Van Gogh and at least one serine/threonine kinase, Dco/CKIε, that is known to regulate PCP. Pp1-87B modulates Van Gogh subcellular localization and directs its dephosphorylation in vivo. PNUTS, a Pp1 regulatory subunit, also modulates PCP. While the direct substrate(s) of Pp1-87B in control of PCP is not known, our data support the model that cycling between phosphorylated and unphosphorylated forms of one or more core PCP components may regulate acquisition of asymmetry. Finally, our screen serves as a resource for identifying additional regulators of PCP signaling.
Topics: Animals; Cell Polarity; Drosophila Proteins; Membrane Proteins; Protein Phosphatase 1; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 37975164
DOI: 10.15252/embr.202356997 -
Cell Reports Aug 2023Feeding behavior is essential for growth and survival of animals; however, relatively little is known about its intrinsic mechanisms. Here, we demonstrate that Gart is...
Feeding behavior is essential for growth and survival of animals; however, relatively little is known about its intrinsic mechanisms. Here, we demonstrate that Gart is expressed in the glia, fat body, and gut and positively regulates feeding behavior via cooperation and coordination. Gart in the gut is crucial for maintaining endogenous feeding rhythms and food intake, while Gart in the glia and fat body regulates energy homeostasis between synthesis and metabolism. These roles of Gart further impact Drosophila lifespan. Importantly, Gart expression is directly regulated by the CLOCK/CYCLE heterodimer via canonical E-box, in which the CLOCKs (CLKs) in the glia, fat body, and gut positively regulate Gart of peripheral tissues, while the core CLK in brain negatively controls Gart of peripheral tissues. This study provides insight into the complex and subtle regulatory mechanisms of feeding and lifespan extension in animals.
Topics: Animals; Circadian Rhythm; Drosophila melanogaster; Drosophila Proteins; Feeding Behavior; Gene Expression Regulation; Homeostasis
PubMed: 37531254
DOI: 10.1016/j.celrep.2023.112912 -
Molecular and Cellular Endocrinology Apr 2024Animals have evolved a multitude of signaling pathways that enable them to orchestrate diverse physiological processes to tightly regulate systemic homeostasis. This... (Review)
Review
Animals have evolved a multitude of signaling pathways that enable them to orchestrate diverse physiological processes to tightly regulate systemic homeostasis. This signaling is mediated by various families of peptide hormones and cytokines that are conserved across the animal kingdom. In this review, we primarily focus on the unpaired (Upd) family of proteins in Drosophila which are evolutionarily related to mammalian leptin and the cytokine interleukin 6. We summarize expression patterns of Upd in Drosophila and discuss the parallels in structure, signaling pathway, and functions between Upd and their mammalian counterparts. In particular, we focus on the roles of Upd in governing metabolic homeostasis, growth and development, and immune responses. We aim to stimulate future studies on leptin-like signaling in other phyla which can help bridge the evolutionary gap between insect Upd and vertebrate leptin and cytokines like interleukin 6.
Topics: Animals; Drosophila; Drosophila Proteins; Leptin; Interleukin-6; Cytokines; Drosophila melanogaster; Mammals
PubMed: 38266772
DOI: 10.1016/j.mce.2024.112165 -
PLoS Biology Oct 2023Morphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be...
Morphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be morphologically plastic. Here, we explored the relationship between glial morphology and transcriptional signature using the Drosophila central nervous system (CNS), where glia are categorised into 5 main classes (outer and inner surface glia, cortex glia, ensheathing glia, and astrocytes), which show within-class morphological diversity. We analysed and validated single-cell RNA sequencing data of Drosophila glia in 2 well-characterised tissues from distinct developmental stages, containing distinct circuit types: the embryonic ventral nerve cord (VNC) (motor) and the adult optic lobes (sensory). Our analysis identified a new morphologically and transcriptionally distinct surface glial population in the VNC. However, many glial morphological categories could not be distinguished transcriptionally, and indeed, embryonic and adult astrocytes were transcriptionally analogous despite differences in developmental stage and circuit type. While we did detect extensive within-class transcriptomic diversity for optic lobe glia, this could be explained entirely by glial residence in the most superficial neuropil (lamina) and an associated enrichment for immune-related gene expression. In summary, we generated a single-cell transcriptomic atlas of glia in Drosophila, and our extensive in vivo validation revealed that glia exhibit more diversity at the morphological level than was detectable at the transcriptional level. This atlas will serve as a resource for the community to probe glial diversity and function.
Topics: Animals; Drosophila; Neuroglia; Neurons; Neuropil; Astrocytes; Drosophila Proteins
PubMed: 37862379
DOI: 10.1371/journal.pbio.3002328 -
Cells Apr 2024Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the... (Review)
Review
Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.
Topics: Animals; Neurofibromatosis 1; Disease Models, Animal; Humans; Drosophila melanogaster; Drosophila Proteins; Neurofibromin 1; Drosophila
PubMed: 38667335
DOI: 10.3390/cells13080721 -
Current Stem Cell Research & Therapy 2024The stem cells' ability to divide asymmetrically to produce differentiating and self-renewing daughter cells is crucial to maintain tissue homeostasis and development.... (Review)
Review
The stem cells' ability to divide asymmetrically to produce differentiating and self-renewing daughter cells is crucial to maintain tissue homeostasis and development. Stem cell maintenance and differentiation rely on their regulatory microenvironment termed 'niches'. The mechanisms of the signal transduction pathways initiated from the niche, regulation of stem cell maintenance and differentiation were quite challenging to study. The knowledge gained from the study of testis and ovary helped develop our understanding of stem cell/niche interactions and signal pathways related to the regulatory mechanisms in maintaining homeostasis of adult tissue. In this review, we discuss the role of signaling pathways in gonadal stem cell regeneration, competition, differentiation, dedifferentiation, proliferation, and fate determination. Furthermore, we present the current knowledge on how these signaling pathways are implicated in cancer, and how they contribute as potential candidates for effective cancer treatment.
Topics: Animals; Female; Male; Drosophila; Drosophila melanogaster; Drosophila Proteins; Signal Transduction; Stem Cells; Cell Differentiation; Stem Cell Niche
PubMed: 36788694
DOI: 10.2174/1574888X18666230213144531