A <i>Drosophila</i> model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells

O’Connor, Reed M.; Stone, Elizabeth F.; Wayne, Charlotte R.; Marcinkevicius, Emily; Ulgherait, Matt; Delventhal, Rebecca; Pantalia, Meghan; Hill, V.; Zhou, Clarice G.; McAllister, Sophie F; Chen, Anna; Ziegenfuss, Jennifer S.; Grueber, Wesley B.; Canman, Julie C.; Shirasu-Hiza, Mimi

doi:10.1083/jcb.201607093

Cited by 31 publications

(38 citation statements)

References 49 publications

(68 reference statements)

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“…For example, in the antennal lobe of Drosophila the morphology and connectivity of local interneurons can vary between animals and may require NG to respond accordingly (Chou et al, 2010). Finally, NG may also play an important role in maintaining axons and in monitoring and pruning synapses to ensure the proper number and type of synaptic connections, as they do in invertebrates (O’Connor et al, 2017) and vertebrates (Risher et al, 2014), respectively, during normal development and after injury (Burda et al, 2016; He and Jin, 2016; Stephan et al, 2012). Glial developmental plasticity may be essential to achieve robustness and maintain homeostasis by readily adapting to these and perhaps other variations in nervous system size and morphology.…”

Section: Discussionmentioning

confidence: 99%

Differing Strategies Despite Shared Lineages of Motor Neurons and Glia to Achieve Robust Development of an Adult Neuropil in Drosophila

Enriquez

Rio

Blazeski

et al. 2018

Neuron

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SUMMARY In vertebrates and invertebrates, neurons and glia are generated in a stereotyped manner from neural stem cells, but the purpose of invariant lineages is not understood. We show that two stem cells that produce leg motor neurons in Drosophila also generate neuropil glia, which wrap and send processes into the neuropil where motor neuron dendrites arborize. The development of the neuropil glia and leg motor neurons is highly coordinated. However, although motor neurons have a stereotyped birth order and transcription factor code, the number and individual morphologies of the glia born from these lineages are highly plastic, yet the final structure they contribute to is highly stereotyped. We suggest that the shared lineages of these two cell types facilitate the assembly of complex neural circuits and that the two birth order strategies—hardwired for motor neurons and flexible for glia—are important for robust nervous system development, homeostasis, and evolution.

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Section: Discussionmentioning

confidence: 99%

Differing Strategies Despite Shared Lineages of Motor Neurons and Glia to Achieve Robust Development of an Adult Neuropil in Drosophila

Enriquez

Rio

Blazeski

et al. 2018

Neuron

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“…To date, no other published work links FMRP and Shrub. However, a recent study demonstrates FMRP regulates synaptic pruning of MB neurons (downstream of PNs) during metamorphosis 69 , a process where Shrub has a pivotal role 26 – 28 . Likewise, the well-studied neuromuscular junction (NMJ) model synapse shows A-D modulation 70 , with established roles for FMRP 11 , 15 and Shrub 24 modulating connectivity during embryonic and larval development.…”

Section: Discussionmentioning

confidence: 99%

ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects

Vita

Broadie

2017

Sci Rep

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The leading cause of heritable intellectual disability (ID) and autism spectrum disorders (ASD), Fragile X syndrome (FXS), is caused by loss of the mRNA-binding translational suppressor Fragile X Mental Retardation Protein (FMRP). In the Drosophila FXS disease model, we found FMRP binds shrub mRNA (human Chmp4) to repress Shrub expression, causing overexpression during the disease state early-use critical period. The FXS hallmark is synaptic overelaboration causing circuit hyperconnectivity. Testing innervation of a central brain learning/memory center, we found FMRP loss and Shrub overexpression similarly increase connectivity. The ESCRT-III core protein Shrub has a central role in endosome-to-multivesicular body membrane trafficking, with synaptic requirements resembling FMRP. Consistently, we found FMRP loss and Shrub overexpression similarly elevate endosomes and result in the arrested accumulation of enlarged intraluminal vesicles within synaptic boutons. Importantly, genetic correction of Shrub levels in the FXS model prevents synaptic membrane trafficking defects and strongly restores innervation. These results reveal a new molecular mechanism underpinning the FXS disease state.

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“…Nevertheless, it may be envisioned that reduced chemokine levels in FXS patients may be associated with a reduced capacity of the immune system of FXS patients to respond to specific pathogens. Of note, one study in the Drosophila melanogaster model of FXS showed that the dfmr1 mutants exhibit increased sensitivity to bacterial infection and decreased phagocytosis of bacteria by systemic immune cells [29], suggesting that dfmr1 gene is required for the activation of phagocytic immune cells and therefore for their immune responsiveness.…”

Section: Reduced Levels Of Pro-inflammatory Chemokines In Fxs Patientsmentioning

confidence: 99%

Reduced serum levels of pro-inflammatory chemokines in fragile X syndrome

et al. 2020

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Background: Fragile X syndrome (FXS) is the most frequent cause of inherited intellectual disability and the most commonly identified monogenic cause of autism. Recent studies have shown that long-term pathological consequences of FXS are not solely confined to the central nervous system (CNS) but rather extend to other physiological dysfunctions in peripheral organs. To gain insights into possible immune dysfunctions in FXS, we profiled a large panel of immune-related biomarkers in the serum of FXS patients and healthy controls. Methods: We have used a sensitive and robust Electro Chemi Luminescence (ECL)-based immunoassay to measure the levels of 52 cytokines in the serum of n = 25 FXS patients and n = 29 healthy controls. We then used univariate statistics and multivariate analysis, as well as an advanced unsupervised clustering method, to identify combinations of immune-related biomarkers that could discriminate FXS patients from healthy individuals. Results: While the majority of the tested cytokines were present at similar levels in FXS patients and healthy individuals, nine chemokines, CCL2, CCL3, CCL4, CCL11, CCL13, CCL17, CCL22, CCL26 and CXCL10, were present at much lower levels in FXS patients. Using robust regression, we show that six of these biomarkers (CCL2, CCL3, CCL11, CCL22, CCL26 and CXCL10) were negatively associated with FXS diagnosis. Finally, applying the K-sparse unsupervised clustering method to the biomarker dataset allowed for the identification of two subsets of individuals, which essentially matched the FXS and healthy control categories. Conclusions: Our data show that FXS patients exhibit reduced serum levels of several chemokines and may therefore exhibit impaired immune responses. The present study also highlights the power of unsupervised clustering methods to identify combinations of biomarkers for diagnosis and prognosis in medicine.

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A Drosophila model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells

Cited by 31 publications

References 49 publications

Differing Strategies Despite Shared Lineages of Motor Neurons and Glia to Achieve Robust Development of an Adult Neuropil in Drosophila

Differing Strategies Despite Shared Lineages of Motor Neurons and Glia to Achieve Robust Development of an Adult Neuropil in Drosophila

ESCRT-III Membrane Trafficking Misregulation Contributes To Fragile X Syndrome Synaptic Defects

Reduced serum levels of pro-inflammatory chemokines in fragile X syndrome

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