Activity-dependent dendritic elaboration requires Pten

Skelton, Patrick D.; Poquérusse, Jessie; Salinaro, Julia; Li, Meijie; Luikart, Bryan W.

doi:10.1016/j.nbd.2019.104703

Cited by 14 publications

(10 citation statements)

References 48 publications

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“…Pten haploinsufficiency leads to increased dendritic arborization with ASD-related social and behavioral deficits ( 58 ). Consistent with previous studies, we found homozygous Pten KO neurons displayed a dramatic increase in dendritic length, neuronal arborization, and increased dendritic spine density as well as spine length ( 5 , 14 , 33 , 56 , 59 ). Our study also examined morphological features in Pten flx/wt ( Pten heterozygous) mice showing increases in dendritic length, arbor complexity and spine density ( Figs.…”

Section: Discussionsupporting

confidence: 92%

“…Confocal images acquired using a Zeiss LSM 510 laser scanning microscope (Zeiss) were analyzed for the total dendritic arborization, the dendritic spine density, and the spine length and pS6 intensity levels as previously described ( 5 , 14 , 59 ). For dendritic arborization analysis, cells on the suprapyramidal blade of the dentate gyrus were imaged with a 2-µm interval and 1,024 × 1,024-pixel resolution using a 20× objective.…”

Section: Methodsmentioning

confidence: 99%

“…For dendritic spine analysis, images were acquired with a 0.5-µm interval and 1,024 × 1,024-pixel resolution using a 63× objective and 3× optical zoom. After image deconvolution (Deconvolution Lab) ( 62 ), the quantification of dendritic spine density was performed with Neuron Studio software ( 14 , 59 , 63 ). For pS6 fluorescence intensity measurement, z-stacks of supra and infrapyramidal blades of dentate gyrus were acquired at 40× with a 1.3-µm oil immersion lens with 0.7× zoom, at 1,024 × 1,024 resolution with a 2-µm z-step.…”

Section: Methodsmentioning

confidence: 99%

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Pten heterozygosity restores neuronal morphology in fragile X syndrome mice

Sathyanarayana

Saunders

Slaughter

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Phosphatase and tensin homolog protein (PTEN) and fragile X mental retardation protein (FMRP) play a vital role in neuronal development and function. This work provides new evidence for the genetic interaction of Pten and Fmr1 in postnatal development of granule neurons and conserved mechanisms across evolution. The observed cellular phenotypic defects in Pten and Fmr1 knockout (KO) could be rectified and restored by heterozygosity of Pten in Fmr1 KO neurons. Additionally, increased expression of PTEN in background Fmr1 KO animals suggests that FMRP negatively regulates PTEN, and we propose that introducing a combination of genetic mutations may normalize structural aspects of neuronal morphology by balancing each other’s expression.

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Section: Discussionsupporting

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pten heterozygosity restores neuronal morphology in fragile X syndrome mice

Sathyanarayana

Saunders

Slaughter

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Murine models of increasing speci city have established that Pten and related downstream signaling participates in the regulation of social behavior, CNS morphology, and neuronal and glial function [23,25,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61]. Consistent behavioral phenotypes of altered social behavior persist when loss of Pten expression is restricted to mature neurons or neuronal precursors, and these models often have impaired learning/memory, increased anxiety, or altered activity/motor ability [16,44,46,48].…”

Section: Discussionmentioning

confidence: 99%

Germline Nuclear-predominant Pten Murine Model Exhibits Impaired Social and Perseverative Behavior, Microglial Activation, and Increased Oxytocinergic Activity

Sarn

Thacker

Lee

et al. 2020

Preprint

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BackgroundAutism spectrum disorder (ASD) has a strong genetic etiology. Germline mutation in the tumor suppressor gene PTEN is one of the best described monogenic risk cases for ASD. Animal modeling of cell-specific Pten loss or mutation has provided insight into how disruptions to the function of PTEN affect neurodevelopment, neurobiology, and social behavior. As such, there is a growing need to understand more about how various aspects of PTEN activity, cell-compartment-specific functions, contribute to certain neurological or behavior phenotypes.MethodsTo understand more about the relationship between Pten localization and downstream effects on neurophenotypes, we generated the nuclear-predominant PtenY68H/+ mouse. We subjected the PtenY68H/+ mouse to morphological and behavioral phenotyping, including the three-chamber sociability and marble burying tests. We subsequently performed in vivo and in vitro cellular phenotyping and concluded the work with a transcriptomic survey of the PtenY68H/+ cortex, which profiled gene expression.ResultsDespite no significant changes in downstream canonical Pten signaling, we found that the PtenY68H/+ mouse presents with macrocephaly, social impairment (i.e., decreased sociability, decreased preference for novel social stimuli, and increased perseverative activity), with significant microglial activation accompanied by enhanced phagocytosis. Because of lack of canonical signaling alterations, we turned to analyzing the neural transcriptomes, which revealed overexpression of many genes involved in neuroinflammation and neuronal function, including oxytocin. Oxytocin transcript was 5-fold overexpressed (P = 0.0018) and oxytocin protein was strongly overexpressed in the PtenY68H/+ hypothalamus. ConclusionsThe nuclear-predominant PtenY68H/+ model has clarified that Pten dysfunction links to microglial pathology and that timed decreased in Pten levels is the provoking insult. Notably, we demonstrate that Pten dysfunction associates with changes in the oxytocin system, an important connection between a prominent ASD risk gene and a potent neuroendocrine regulator of social behavior. Ultimately, the findings from this work may reveal important biomarkers and/or novel therapeutic modalities that could be explored in individuals with germline mutations in PTEN with ASD.

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“…The functional roles of the newly synthetized proteins need to be determined in the future. As the dendritic architecture depends on many different signaling pathways and molecular mechanisms (Arikkath, 2012;Skelton, Poquerusse, Salinaro, Li, & Luikart, 2020;Ziegler & Tavosanis, 2019). The contribution of specific molecules and proteins contained in sEVs on it deserves many future studies.…”

Section: Functional Effect Of Astrocyte-derived Sevs On Neuronsmentioning

confidence: 99%

SUMOylation regulates protein cargo in Astrocyte-derived small extracellular vesicles

Fernández¹,

Mendez²,

Santis³

et al. 2020

Preprint

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Recent studies have described a new mechanism of intercellular communication mediated by various types of extracellular vesicles (EVs). In particular, exosomes are small EVs (sEVs) released to the extracellular environment by the fusion of the endosomal pathway-related multivesicular bodies (containing intraluminal vesicles) with the plasma membrane. sEVs contain a molecular cargo consisting of lipids, proteins, and nucleic acids. However, the loading mechanisms for this complex molecular cargo have not yet been completely elucidated. In that line, the post translational modification SUMO (Small Ubiquitin-like Modifier) has been shown to impact the incorporation of select proteins into sEVs. We therefore decided to investigate whether SUMOylation is a mechanism that defines protein loading to sEVs. In order to investigate the role of SUMOylation in cargo loading into sEVs, we utilized astrocytes, an essential cell type of the central nervous system with homeostatic functions, to study the impact of SUMOylation on the protein cargo of sEVs. Following SUMO overexpression, achieved by transfection of SUMO plasmids or experimental conditions that modulate SUMOylation in primary astrocyte cultures, we detected proteins related to cell division, translation, and transcription by mass-spectrometry. In astrocyte cultures treated with the general SUMOylation inhibitor 2-D08 (2′,3′,4′-trihydroxy-flavone, 2-(2,3,4-Trihydroxyphenyl)-4H-1-Benzopyran-4-one) we observed an increase in the number of sEVs and a decreased amount of protein cargo within them. In turn, in astrocytes treated with the stress hormone corticosterone, we found an increase of SUMO-2 conjugated proteins and sEVs from these cells contained an augmented protein cargo. In this case, the proteins detected with mass-spectrometry were mostly proteins related to protein translation. To test whether astrocyte-derived sEVs obtained in these experimental conditions could modulate protein synthesis in target cells, we incubated primary neurons with astrocyte-derived sEVs. sEVs from corticosterone-treated astrocytes stimulated protein synthesis while no difference was found with sEVs derived from 2-D08-treated astrocytes. Our results show that SUMO conjugation plays a fundamental role in defining the protein cargo of sEVs impacting the physiological function of target cells.

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Activity-dependent dendritic elaboration requires Pten

Cited by 14 publications

References 48 publications

Pten heterozygosity restores neuronal morphology in fragile X syndrome mice

Pten heterozygosity restores neuronal morphology in fragile X syndrome mice

Germline Nuclear-predominant Pten Murine Model Exhibits Impaired Social and Perseverative Behavior, Microglial Activation, and Increased Oxytocinergic Activity

SUMOylation regulates protein cargo in Astrocyte-derived small extracellular vesicles

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