Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



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Graphene/Semiconductor Hybrid Heterostructures for Optoelectronic Device Applications

Publication date: Available online 28 February 2018
Source:Nano Today
Author(s): Chao Xie, Yi Wang, Zhi-Xiang Zhang, Di Wang, Lin-Bao Luo
As one of the most appealing two-dimensional materials, graphene (Gr) has attracted tremendous research interest in optoelectronic device applications for its plenty of exceptional electrical and optical properties. The emergence of Gr/semiconductor hybrid heterostructures provides a promising platform for assembling high-performance optoelectronic devices that can overcome intrinsic limitations of Gr. However, although significant achievements have been made, many challenges still exist. Here, we comprehensively review the progress in the development of various optoelectronic devices based on Gr/semiconductor hybrid heterostructures, including /group II-VI nanostructures, /group III-V semiconductors, /group IV semiconductors, /metal oxides and /other semiconductors, in terms of the device design, device performance and physics, processing techniques for performance optimization, etc. In the final section, conclusions of the existing techniques are presented and future challenges in optoelectronic applications of Gr/semiconductor hybrid heterostructures are addressed.

Graphical abstract

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Volitional and Automatic Control of the Hand When Reaching to Grasp Objects.

Author: Chen, Zhongting; Saunders, Jeffrey Allen

DOI: 10.1037/xhp0000492

Publication Date: POST AUTHOR CORRECTIONS, 26 February 2018

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Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



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SREBPs in Lipid Metabolism, Insulin Signaling, and Beyond

Publication date: Available online 27 February 2018
Source:Trends in Biochemical Sciences
Author(s): Russell A. DeBose-Boyd, Jin Ye
Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that activate genes encoding enzymes required for synthesis of cholesterol and unsaturated fatty acids. SREBPs are controlled by multiple mechanisms at the level of mRNA synthesis, proteolytic activation, and transcriptional activity. In this review, we summarize the recent findings that contribute to the current understanding of the regulation of SREBPs and their physiologic roles in maintenance of lipid homeostasis, insulin signaling, innate immunity, and cancer development.



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Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Curcumin restrains hepatic glucose production by blocking cAMP/PKA signaling and reducing acetyl CoA accumulation in high-fat diet (HFD)-fed mice

Publication date: Available online 27 February 2018
Source:Molecular and Cellular Endocrinology
Author(s): Zixia Wang, Dan Xu, Linlin She, Yirui Zhang, Qingli Wei, Jiye Aa, Guangji Wang, Baolin Liu, Yuan Xie
ObjectiveThis study is designed to investigate whether curcumin reduces excessive hepatic glucose production (HGP) via regulation of second messenger cAMP.MethodsHigh-fat diet (HFD)-fed mice were orally administrated of metformin (200 mg/kg) or curcumin (50 mg/kg) daily for 10 weeks. Meanwhile, we stimulated mouse primary hepatocytes with palmitate (PA).ResultsCurcumin reduced hepatic cAMP accumulation by preserving PDE4B induction, thereby suppressing gluconeogenesis via blocking cAMP/PKA activation. Curcumin reduced lipid deposition by reducing free fatty acid uptake and prevented acetyl CoA accumulation by combating mitochondrial oxidation. As a result from inhibiting acetyl CoA accumulation, curcumin protected pyruvate dehydrogenase (PDH) activity and inhibited pyruvate carboxylase (PC), limiting the shift of mitochondrial pyruvate from oxidation to gluconeogenesis via the carboxylation.ConclusionCurcumin reduced cAMP accumulation by preserving PDE4B activity and inhibited acetyl CoA production by reducing mitochondrial fatty acid oxidation, thereby restraining pyruvate-driven hepatic glucose production.



http://ift.tt/2CMaxX6

Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Aishwarya Pawar, Paradesi Naidu Gollavilli, Shaomeng Wang, Irfan A. Asangani
BRD4 plays a major role in the transcription networks orchestrated by androgen receptor (AR) in castration-resistant prostate cancer (CRPC). Several BET inhibitors (BETi) that displace BRD4 from chromatin are being evaluated in clinical trials for CRPC. Here, we describe mechanisms of acquired resistance to BETi that are amenable to targeted therapies in CRPC. BETi-resistant CRPC cells displayed cross-resistance to a variety of BETi in the absence of gatekeeper mutations, exhibited reduced chromatin-bound BRD4, and were less sensitive to BRD4 degraders/knockdown, suggesting a BRD4-independent transcription program. Transcriptomic analysis revealed reactivation of AR signaling due to CDK9-mediated phosphorylation of AR, resulting in sensitivity to CDK9 inhibitors and enzalutamide. Additionally, increased DNA damage associated with PRC2-mediated transcriptional silencing of DDR genes was observed, leading to PARP inhibitor sensitivity. Collectively, our results identify the therapeutic limitation of BETi as a monotherapy; however, our BETi resistance data suggest unique opportunities for combination therapies in treating CRPC.

Graphical abstract

Teaser

Resistance to targeted therapies is a major problem. Pawar et al. investigate the potential mechanisms of acquired resistance to BET inhibitors in prostate cancer and identify actionable targets to overcome the resistance. This study highlights the therapeutic limitation of BET inhibitors as a monotherapy and suggests potential combination therapies in treating prostate cancer.


http://ift.tt/2GMIqJO

SynDIG4/Prrt1 Is Required for Excitatory Synapse Development and Plasticity Underlying Cognitive Function

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Lucas Matt, Lyndsey M. Kirk, George Chenaux, David J. Speca, Kyle R. Puhger, Michael C. Pride, Mohammad Qneibi, Tomer Haham, Kristopher E. Plambeck, Yael Stern-Bach, Jill L. Silverman, Jacqueline N. Crawley, Johannes W. Hell, Elva Díaz
Altering AMPA receptor (AMPAR) content at synapses is a key mechanism underlying the regulation of synaptic strength during learning and memory. Previous work demonstrated that SynDIG1 (synapse differentiation-induced gene 1) encodes a transmembrane AMPAR-associated protein that regulates excitatory synapse strength and number. Here we show that the related protein SynDIG4 (also known as Prrt1) modifies AMPAR gating properties in a subunit-dependent manner. Young SynDIG4 knockout (KO) mice have weaker excitatory synapses, as evaluated by immunocytochemistry and electrophysiology. Adult SynDIG4 KO mice show complete loss of tetanus-induced long-term potentiation (LTP), while mEPSC amplitude is reduced by only 25%. Furthermore, SynDIG4 KO mice exhibit deficits in two independent cognitive assays. Given that SynDIG4 colocalizes with the AMPAR subunit GluA1 at non-synaptic sites, we propose that SynDIG4 maintains a pool of extrasynaptic AMPARs necessary for synapse development and function underlying higher-order cognitive plasticity.

Graphical abstract

Teaser

Matt et al. show that mice lacking the AMPAR-associated protein SynDIG4/Prrt1 display deficits in synaptic plasticity and cognition. SynDIG4 modifies AMPAR biophysical properties in heterologous cells, but synaptic AMPAR kinetics are unchanged, suggesting that SynDIG4 establishes a pool of extrasynaptic AMPARs necessary for higher-order cognitive plasticity.


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A NuRD Complex from Xenopus laevis Eggs Is Essential for DNA Replication during Early Embryogenesis

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Christo P. Christov, Kevin S. Dingwell, Mark Skehel, Helen S. Wilkes, Julian E. Sale, James C. Smith, Torsten Krude
DNA replication in the embryo of Xenopus laevis changes dramatically at the mid-blastula transition (MBT), with Y RNA-independent random initiation switching to Y RNA-dependent initiation at specific origins. Here, we identify xNuRD, an MTA2-containing assemblage of the nucleosome remodeling and histone deacetylation complex NuRD, as an essential factor in pre-MBT Xenopus embryos that overcomes a functional requirement for Y RNAs during DNA replication. Human NuRD complexes have a different subunit composition than xNuRD and do not support Y RNA-independent initiation of DNA replication. Blocking or immunodepletion of xNuRD inhibits DNA replication initiation in isolated nuclei in vitro and causes inhibition of DNA synthesis, developmental delay, and embryonic lethality in early embryos. xNuRD activity declines after the MBT, coinciding with dissociation of the complex and emergence of Y RNA-dependent initiation. Our data thus reveal an essential role for a NuRD complex as a DNA replication factor during early Xenopus development.

Graphical abstract

Teaser

Christov et al. show that the chromatin remodeling complex xNuRD is an essential DNA replication factor in the eggs and early embryos of Xenopus laevis. They demonstrate that xNuRD can initiate DNA replication in the absence of non-coding Y RNAs, which only become essential for replication later in development.


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Nap1l1 Controls Embryonic Neural Progenitor Cell Proliferation and Differentiation in the Developing Brain

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): Huimin Qiao, Yanxin Li, Chao Feng, Shuguang Duo, Fen Ji, Jianwei Jiao
The precise function and role of nucleosome assembly protein 1-like 1 (Nap1l1) in brain development are unclear. Here, we find that Nap1l1 knockdown decreases neural progenitor cell (NPC) proliferation and induces premature neuronal differentiation during cortical development. A similar deficiency in embryonic neurogenesis was observed in Nap1l1 knockout (KO) mice, which were generated using the CRISPR-Cas9 system. RNA sequencing (RNA-seq) analysis indicates that Ras-associated domain family member 10 (RassF10) may be the downstream target of Nap1l1. Furthermore, we found that Nap1l1 regulates RassF10 expression by promoting SETD1A-mediated H3K4 trimethylation at the RassF10 promoter. Nap1l1 KO defects may be rescued by RassF10 overexpression, suggesting that Nap1l1 controls NPC differentiation through RassF10. Our findings reveal an essential role for the Nap1l1 histone chaperone in cortical neurogenesis during early embryonic brain development.

Graphical abstract

Teaser

Nap1l1 plays essential roles in embryonic neurogenesis, including the proliferation and differentiation of neural progenitors. Qiao et al. find that Nap1l1 regulates RassF10 through SETD1A-mediated H3K4me3 of the RassF10 promoter.


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