Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation

Farhy-Tselnicker, Isabella; Casteren, Adriana van; Lee, Aletheia; Chang, Veronica T.; Aricescu, A. Radu; Allen, Nicola J.

doi:10.1016/j.neuron.2017.09.053

Cited by 166 publications

(162 citation statements)

References 62 publications

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“…The time window of astrocyte maturation overlaps with the period of synapse formation. Astrocytes secrete important protein signals that induce synapse formation (Allen et al, ; Blanco‐Suarez, Liu, Kopelevich, & Allen, ; Christopherson et al, ; Eroglu et al, ; Farhy‐Tselnicker et al, ; Kucukdereli et al, ; Pfrieger & Barres, ; Stogsdill et al, ; Ullian et al, ). To test whether HBEGF, EGFR, and P53 affect astrocytic interaction with synapses, we examined the expression of genes synapse‐inducing proteins.…”

Section: Resultsmentioning

confidence: 99%

“…Long thought to be passive support cells, astrocytes have been recently shown to be critical for the development and function of the central nervous system. Astrocytes promote neuron survival (Banker, 1980), stimulate synapse formation and function (Allen, 2014;Allen et al, 2012;Allen & Eroglu, 2017;Chung, Allen, & Eroglu, 2015;Eroglu et al, 2009;Farhy-Tselnicker et al, 2017;Khakh & McCarthy, 2015;Kucukdereli et al, 2011;Molofsky et al, 2014;Pfrieger & Barres, 1997;Singh et al, 2016;Stogsdill et al, 2017;Ullian, Sapperstein, Christopherson, & Barres, 2001), and engulf extra synapses formed during development (Chung et al, 2013;Vainchtein et al, 2018). Furthermore, astrocytes are important for neural transmitter recycling (Maragakis & Rothstein, 2004;Rothstein et al, 1994), ion and water homeostasis, synaptic transmission, synaptic plasticity (Haydon & Nedergaard, 2015;Nedergaard, 1994), the integrity of the blood brain barrier, and the regulation of blood flow (Takano et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Khankan

Caneda

et al. 2019

Glia

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Astrocytes are critical for the development and function of the central nervous system. In developing brains, immature astrocytes undergo morphological, molecular, cellular, and functional changes as they mature. Although the mechanisms that regulate the maturation of other major cell types in the central nervous system such as neurons and oligodendrocytes have been extensively studied, little is known about the cellular and molecular mechanisms that control astrocyte maturation. Here, we identified molecular markers of astrocyte maturation and established an in vitro assay for studying the mechanisms of astrocyte maturation. Maturing astrocytes in vitro exhibit similar molecular changes and represent multiple molecular subtypes of astrocytes found in vivo. Using this system, we found that astrocyte‐to‐astrocyte contact strongly promotes astrocyte maturation. In addition, secreted signals from microglia, oligodendrocyte precursor cells, or endothelial cells affect a small subset of astrocyte genes but do not consistently change astrocyte maturation. To identify molecular mechanisms underlying astrocyte maturation, we treated maturing astrocytes with molecules that affect the function of tumor‐associated genes. We found that a positive feedback loop of heparin‐binding epidermal growth factor‐like growth factor (HBEGF) and epidermal growth factor receptor (EGFR) signaling regulates astrocytes maturation. Furthermore, HBEGF, EGFR, and tumor protein 53 (TP53) affect the expression of genes important for cilium development, the circadian clock, and synapse function. These results revealed cellular and molecular mechanisms underlying astrocytes maturation with implications for the understanding of glioblastoma.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Khankan

Caneda

et al. 2019

Glia

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“…Data are from one experiment out of three performed. These data indicate that lack of endogenous PTX3 results in defective synapse functioning, which apparently cannot be rescued by other astrocyte-derived factors expressed at later developmental stages (Kucukdereli et al, 2011;Allen et al, 2012;Farhy-Tselnicker et al, 2017). Binding of PTX3 N-term domain was performed on TSP1 immobilized on plastic wells.…”

Section: Of 20mentioning

confidence: 97%

Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1‐integrin

et al. 2018

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Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte‐secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post‐synaptically silent, suggesting that completion of early synaptogenesis may require a two‐step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain. PTX3 plays a key role in promoting functionally‐active CNS synapses, by increasing the surface levels and synaptic clustering of AMPA glutamate receptors. This process involves tumor necrosis factor‐induced protein 6 (TSG6), remodeling of the perineuronal network, and a β1‐integrin/ERK pathway. Furthermore, PTX3 activity is regulated by TSP1, which directly interacts with the N‐terminal region of PTX3. These data unveil a fundamental role of PTX3 in promoting the first wave of synaptogenesis, and show that interplay of TSP1 and PTX3 sets the proper balance between synaptic growth and synapse function in the developing brain.

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“…Astrocyte-secreted glypican 4, which induces synapse formation by first clustering GluA1 AMPA receptors, acts by signaling through the protein phosphatase receptor PTPRδ present in the presynaptic terminal. This leads to release of the AMPA receptor clustering factor neuronal pentraxin 1, which then binds to postsynaptic GluA1 AMPA receptors and stabilizes them on the surface to induce synapse formation (Farhy-Tselnicker et al, 2017). …”

Section: How Do Neurons Respond To Astrocyte Synaptogenic Cues?mentioning

confidence: 99%

Cell Biology of Astrocyte-Synapse Interactions

Allen

Eroğlu

2017

Neuron

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827

603

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Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we will pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development.

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Astrocyte-Secreted Glypican 4 Regulates Release of Neuronal Pentraxin 1 from Axons to Induce Functional Synapse Formation

Cited by 166 publications

References 62 publications

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Astrocyte‐to‐astrocyte contact and a positive feedback loop of growth factor signaling regulate astrocyte maturation

Pentraxin 3 regulates synaptic function by inducing AMPA receptor clustering via ECM remodeling and β1‐integrin

Cell Biology of Astrocyte-Synapse Interactions

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