Cell Biology (Scheiffele)Head of Research Unit Prof. Dr.Peter ScheiffeleOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 32 foundShow per page10 10 20 50 Molecular Mechanisms of Neuronal Synapse Formation Research Project | 1 Project MembersImported from Grants Tool 4698088 Targeting selective mRNA translation for novel therapeutics in Autism Spectrum Disorders Research Project | 1 Project MembersImported from Grants Tool 4702406 Cellular and circuit underpinnings of social and maternal behaviours Research Project | 1 Project MembersNo Description available Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism. EMBO Fellowship for Myrto Panopoulou Research Project | 2 Project MembersNo Description available Control of molecular differentiation programs by spontaneous activity in neocortical development Research Project | 1 Project MembersThe formation of sensory cortical circuits in the mammalian brain is largely completed at the onset of sensation, with individual cortical neurons exhibiting specific and selective response properties that undergo only minor refinement thereafter. Before sensation, all sensory systems exhibit spontaneous patterned activity that propagates through ascending sensory pathways to primary cortical areas. The structure and spatio-temporal dynamics of such spontaneous patterned activity are thought to have a major impact on cortical wiring. Simultaneously, with spontaneous activity, transcriptional programs unfold that specify cortical cell types, steer their anatomical projections, and may instruct wiring specificity. Alternative mRNA splicing has emerged as a central post-transcriptional mechanism for expanding the molecular codes for neuronal wiring and synapse specification. Moreover, alterations in alternative splicing programs have been linked to neurodevelopmental disorders, in particular autism. It is unknown how spontaneous activity, transcriptional and - in particular - alternative splicing programs interact to drive neuronal wiring in cortex. In this project, we will use the mouse visual cortex as a model system to address these fundamental questions. In Aim 1, we will use in vivo two-photon calcium imaging of individual neurons to map developmental emergence of spontaneous patterned activity and will correlate spontaneous activity patterns to cell type-specific transcript isoform programs. In Aim 2, we will shift patterns of spontaneous activity in the retina and will develop novel genetic sparse marking approaches to explore the impact of patterned activity on transcript isoform programs and neuronal wiring. In Aim 3, we will uncover mechanisms underlying neuronal activity-dependent alternative splicing regulation by advancing novel genetically targeted in vivo methods for dissecting RNA-protein interactions. Together these experiments will illuminate how spontaneous activity in developing sensory systems instructs alternative splicing programs and will advance our understanding of how developmental processes mediate the acquisition of functional specificity in mature cortical networks. Finally, the results will have a profound impact on the interpretation of alternative splicing and network level defects underlying neurodevelopmental diseases. Role of regulated intron retentions during neuronal plasticity and learning Research Project | 1 Project MembersUpon experience, humans can learn, acquire new skills and adapt to their environment. This is explained by the exceptional plasticity of the brain. When neurons receive a message, they trigger cellular programs aiming to modify their structure and functioning. These cellular modifications represent the physical support of learning. Understanding which molecular mechanisms that allow this cellular plasticity is a major challenge. Transcription programs induced by neuronal stimulation are crucial for plasticity. However, one poorly appreciated aspect of transcription is its significant temporal constraint. Synthesis of RNAs can require many hours, especially for long genes whose expression is overrepresented in the brain. Therefore, the impact of new transcription is drastically limited in respect to the rapid plastic events that occurs in seconds/minutes range. I previously discovered a transcription-independent mechanism that rapidly regulates gene expression in response to neuronal stimulation. This mechanism relies on nuclear storage of pre-existing transcripts and their rapid mobilization in response to signals. In primary neurons, we observed that a substantial population of transcripts retains select introns. Intron corresponds to a non-coding part of transcript that needs to be removed by splicing to generate a mature mRNA. At rest, these intron-retaining transcripts are stably maintained in the nucleus. However, upon neuronal stimulation, these RNAs finalize their splicing in few minutes and are subsequently used for protein production. The discovery of this new mechanism has opened unsuspected tracks in respect to the molecular pathways contributing to learning. The goal of this proposal is to explore to which extent intron retention and excision is deployed in living animals and how it contributes to neuronal plasticity. First, I will use transcriptome-wide methods as well as single-molecule RNA visualization approaches to probe in vivo intron retention profiles and their regulation under physiological stimulation . Second, I will combine a targeted analysis of the public data from the recently updated Encode consortium, and the elaboration of minigene assays to identify the regulatory determinants of intron retention and excision . Ultimately, I will elaborate selective antisense oligonucleotides and apply them in living animals with high-precision surgical procedures to control intron patterns and explore the impact of intron regulation on neuron biology in mouse . Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors Research Project | 1 Project MembersWith an estimate incidence of 1 in 100 children, autism spectrum disorders represent an enormous burden on the population. These developmental disorders develop in the first years of life and to date no mechanism-based treatments are available to the patients. One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. Recent work highlighted an unexpected convergence in pathophysiology between gene products contributing to seemingly distant cellular functions. Thus, findings from model organisms suggest that mutations in autism-associated synaptic components precipitate alterations in translational regulation which resemble dysfunctions emerging from direct genetic alterations in the mRNA translation machinery. Early work conceptualized translational de-regulation as representing "too high" or "too low" levels of translation. However, based on more recent evidence it is now hypothesized that alterations in translation machinery and cell signaling result in a selective translational de-regulation of specific mRNAs which are fundamental drivers of the pathophysiology of the disorders. Endogenous RNA-based sensors for neuronal homeostasis and plasticity. Research Project | 1 Project MembersNeurons undergo profound plastic modifications but, at the same time, retain stable intrinsic properties. This implies sensing, signaling and homeostatic mechanisms that couple signaling to gene regulation. In this proposal I will examine a novel mechanism for transcriptional homeostasis in mammalian neurons. Specifically, I will test the hypothesis that the degradation of a class of intron-containing mRNAs contributes to a sensing mechanism that shapes the neuronal transcriptome. There is strong evidence of the link between mRNA decay factors in the cytoplasm and the regulation of gene transcription in the nuclei. Very recent discoveries link mutant mRNA decay by Nonsense Mediated Decay (NMD) with upregulation of the expression of genes with similar sequences, a process named Genetic Compensation (GC). One recently described class of endogenous transcripts destined for NMD arises from intron retention during alternative splicing . Roles for icRNA in nuclei and cytoplasm have been discovered, but most cytoplasmic icRNA are targeted by NMD, and their functional relevance remains a mystery. In analogy to the genetic compensation mechanism in mutant mRNAs, I hypothesize that degradation of endogenous cytoplasmic icRNAs triggers modifications of the neuronal transcriptome. Thus, cytoplasmic icRNAs would act as sensors for neuronal gene expression that signal the state of the cytosolic transcriptome and translatome back to the nucleus to achieve neuronal homeostasis. Using transgenic mouse lines, adenoviral-mediated knock-down and overexpression of reporter genes in cultured cortical neurons and RNA-Seq I will: (1) check whether GC works in post-mitotic neurons, (2) uncover endogenously degraded mRNA role in gene expression regulation. Endogenous RNA-based sensors for neuronal homeostasis and plasticity. Research Project | 1 Project MembersImported from Grants Tool 4599654 1234 1...4 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 32 foundShow per page10 10 20 50 Molecular Mechanisms of Neuronal Synapse Formation Research Project | 1 Project MembersImported from Grants Tool 4698088 Targeting selective mRNA translation for novel therapeutics in Autism Spectrum Disorders Research Project | 1 Project MembersImported from Grants Tool 4702406 Cellular and circuit underpinnings of social and maternal behaviours Research Project | 1 Project MembersNo Description available Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism. EMBO Fellowship for Myrto Panopoulou Research Project | 2 Project MembersNo Description available Control of molecular differentiation programs by spontaneous activity in neocortical development Research Project | 1 Project MembersThe formation of sensory cortical circuits in the mammalian brain is largely completed at the onset of sensation, with individual cortical neurons exhibiting specific and selective response properties that undergo only minor refinement thereafter. Before sensation, all sensory systems exhibit spontaneous patterned activity that propagates through ascending sensory pathways to primary cortical areas. The structure and spatio-temporal dynamics of such spontaneous patterned activity are thought to have a major impact on cortical wiring. Simultaneously, with spontaneous activity, transcriptional programs unfold that specify cortical cell types, steer their anatomical projections, and may instruct wiring specificity. Alternative mRNA splicing has emerged as a central post-transcriptional mechanism for expanding the molecular codes for neuronal wiring and synapse specification. Moreover, alterations in alternative splicing programs have been linked to neurodevelopmental disorders, in particular autism. It is unknown how spontaneous activity, transcriptional and - in particular - alternative splicing programs interact to drive neuronal wiring in cortex. In this project, we will use the mouse visual cortex as a model system to address these fundamental questions. In Aim 1, we will use in vivo two-photon calcium imaging of individual neurons to map developmental emergence of spontaneous patterned activity and will correlate spontaneous activity patterns to cell type-specific transcript isoform programs. In Aim 2, we will shift patterns of spontaneous activity in the retina and will develop novel genetic sparse marking approaches to explore the impact of patterned activity on transcript isoform programs and neuronal wiring. In Aim 3, we will uncover mechanisms underlying neuronal activity-dependent alternative splicing regulation by advancing novel genetically targeted in vivo methods for dissecting RNA-protein interactions. Together these experiments will illuminate how spontaneous activity in developing sensory systems instructs alternative splicing programs and will advance our understanding of how developmental processes mediate the acquisition of functional specificity in mature cortical networks. Finally, the results will have a profound impact on the interpretation of alternative splicing and network level defects underlying neurodevelopmental diseases. Role of regulated intron retentions during neuronal plasticity and learning Research Project | 1 Project MembersUpon experience, humans can learn, acquire new skills and adapt to their environment. This is explained by the exceptional plasticity of the brain. When neurons receive a message, they trigger cellular programs aiming to modify their structure and functioning. These cellular modifications represent the physical support of learning. Understanding which molecular mechanisms that allow this cellular plasticity is a major challenge. Transcription programs induced by neuronal stimulation are crucial for plasticity. However, one poorly appreciated aspect of transcription is its significant temporal constraint. Synthesis of RNAs can require many hours, especially for long genes whose expression is overrepresented in the brain. Therefore, the impact of new transcription is drastically limited in respect to the rapid plastic events that occurs in seconds/minutes range. I previously discovered a transcription-independent mechanism that rapidly regulates gene expression in response to neuronal stimulation. This mechanism relies on nuclear storage of pre-existing transcripts and their rapid mobilization in response to signals. In primary neurons, we observed that a substantial population of transcripts retains select introns. Intron corresponds to a non-coding part of transcript that needs to be removed by splicing to generate a mature mRNA. At rest, these intron-retaining transcripts are stably maintained in the nucleus. However, upon neuronal stimulation, these RNAs finalize their splicing in few minutes and are subsequently used for protein production. The discovery of this new mechanism has opened unsuspected tracks in respect to the molecular pathways contributing to learning. The goal of this proposal is to explore to which extent intron retention and excision is deployed in living animals and how it contributes to neuronal plasticity. First, I will use transcriptome-wide methods as well as single-molecule RNA visualization approaches to probe in vivo intron retention profiles and their regulation under physiological stimulation . Second, I will combine a targeted analysis of the public data from the recently updated Encode consortium, and the elaboration of minigene assays to identify the regulatory determinants of intron retention and excision . Ultimately, I will elaborate selective antisense oligonucleotides and apply them in living animals with high-precision surgical procedures to control intron patterns and explore the impact of intron regulation on neuron biology in mouse . Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors Research Project | 1 Project MembersWith an estimate incidence of 1 in 100 children, autism spectrum disorders represent an enormous burden on the population. These developmental disorders develop in the first years of life and to date no mechanism-based treatments are available to the patients. One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. Recent work highlighted an unexpected convergence in pathophysiology between gene products contributing to seemingly distant cellular functions. Thus, findings from model organisms suggest that mutations in autism-associated synaptic components precipitate alterations in translational regulation which resemble dysfunctions emerging from direct genetic alterations in the mRNA translation machinery. Early work conceptualized translational de-regulation as representing "too high" or "too low" levels of translation. However, based on more recent evidence it is now hypothesized that alterations in translation machinery and cell signaling result in a selective translational de-regulation of specific mRNAs which are fundamental drivers of the pathophysiology of the disorders. Endogenous RNA-based sensors for neuronal homeostasis and plasticity. Research Project | 1 Project MembersNeurons undergo profound plastic modifications but, at the same time, retain stable intrinsic properties. This implies sensing, signaling and homeostatic mechanisms that couple signaling to gene regulation. In this proposal I will examine a novel mechanism for transcriptional homeostasis in mammalian neurons. Specifically, I will test the hypothesis that the degradation of a class of intron-containing mRNAs contributes to a sensing mechanism that shapes the neuronal transcriptome. There is strong evidence of the link between mRNA decay factors in the cytoplasm and the regulation of gene transcription in the nuclei. Very recent discoveries link mutant mRNA decay by Nonsense Mediated Decay (NMD) with upregulation of the expression of genes with similar sequences, a process named Genetic Compensation (GC). One recently described class of endogenous transcripts destined for NMD arises from intron retention during alternative splicing . Roles for icRNA in nuclei and cytoplasm have been discovered, but most cytoplasmic icRNA are targeted by NMD, and their functional relevance remains a mystery. In analogy to the genetic compensation mechanism in mutant mRNAs, I hypothesize that degradation of endogenous cytoplasmic icRNAs triggers modifications of the neuronal transcriptome. Thus, cytoplasmic icRNAs would act as sensors for neuronal gene expression that signal the state of the cytosolic transcriptome and translatome back to the nucleus to achieve neuronal homeostasis. Using transgenic mouse lines, adenoviral-mediated knock-down and overexpression of reporter genes in cultured cortical neurons and RNA-Seq I will: (1) check whether GC works in post-mitotic neurons, (2) uncover endogenously degraded mRNA role in gene expression regulation. Endogenous RNA-based sensors for neuronal homeostasis and plasticity. Research Project | 1 Project MembersImported from Grants Tool 4599654 1234 1...4
Molecular Mechanisms of Neuronal Synapse Formation Research Project | 1 Project MembersImported from Grants Tool 4698088
Targeting selective mRNA translation for novel therapeutics in Autism Spectrum Disorders Research Project | 1 Project MembersImported from Grants Tool 4702406
Cellular and circuit underpinnings of social and maternal behaviours Research Project | 1 Project MembersNo Description available
Development of brain-penetrant MNK inhibitors Research Project | 3 Project MembersMAP-kinase interacting kinases (MNKs) are a novel target for the treatment of autism spectrum disorders. We aim to develop a brain-penetrant, small molecule inhibitor that selectively targets MNKs and alleviates the core symptoms of autism.
Control of molecular differentiation programs by spontaneous activity in neocortical development Research Project | 1 Project MembersThe formation of sensory cortical circuits in the mammalian brain is largely completed at the onset of sensation, with individual cortical neurons exhibiting specific and selective response properties that undergo only minor refinement thereafter. Before sensation, all sensory systems exhibit spontaneous patterned activity that propagates through ascending sensory pathways to primary cortical areas. The structure and spatio-temporal dynamics of such spontaneous patterned activity are thought to have a major impact on cortical wiring. Simultaneously, with spontaneous activity, transcriptional programs unfold that specify cortical cell types, steer their anatomical projections, and may instruct wiring specificity. Alternative mRNA splicing has emerged as a central post-transcriptional mechanism for expanding the molecular codes for neuronal wiring and synapse specification. Moreover, alterations in alternative splicing programs have been linked to neurodevelopmental disorders, in particular autism. It is unknown how spontaneous activity, transcriptional and - in particular - alternative splicing programs interact to drive neuronal wiring in cortex. In this project, we will use the mouse visual cortex as a model system to address these fundamental questions. In Aim 1, we will use in vivo two-photon calcium imaging of individual neurons to map developmental emergence of spontaneous patterned activity and will correlate spontaneous activity patterns to cell type-specific transcript isoform programs. In Aim 2, we will shift patterns of spontaneous activity in the retina and will develop novel genetic sparse marking approaches to explore the impact of patterned activity on transcript isoform programs and neuronal wiring. In Aim 3, we will uncover mechanisms underlying neuronal activity-dependent alternative splicing regulation by advancing novel genetically targeted in vivo methods for dissecting RNA-protein interactions. Together these experiments will illuminate how spontaneous activity in developing sensory systems instructs alternative splicing programs and will advance our understanding of how developmental processes mediate the acquisition of functional specificity in mature cortical networks. Finally, the results will have a profound impact on the interpretation of alternative splicing and network level defects underlying neurodevelopmental diseases.
Role of regulated intron retentions during neuronal plasticity and learning Research Project | 1 Project MembersUpon experience, humans can learn, acquire new skills and adapt to their environment. This is explained by the exceptional plasticity of the brain. When neurons receive a message, they trigger cellular programs aiming to modify their structure and functioning. These cellular modifications represent the physical support of learning. Understanding which molecular mechanisms that allow this cellular plasticity is a major challenge. Transcription programs induced by neuronal stimulation are crucial for plasticity. However, one poorly appreciated aspect of transcription is its significant temporal constraint. Synthesis of RNAs can require many hours, especially for long genes whose expression is overrepresented in the brain. Therefore, the impact of new transcription is drastically limited in respect to the rapid plastic events that occurs in seconds/minutes range. I previously discovered a transcription-independent mechanism that rapidly regulates gene expression in response to neuronal stimulation. This mechanism relies on nuclear storage of pre-existing transcripts and their rapid mobilization in response to signals. In primary neurons, we observed that a substantial population of transcripts retains select introns. Intron corresponds to a non-coding part of transcript that needs to be removed by splicing to generate a mature mRNA. At rest, these intron-retaining transcripts are stably maintained in the nucleus. However, upon neuronal stimulation, these RNAs finalize their splicing in few minutes and are subsequently used for protein production. The discovery of this new mechanism has opened unsuspected tracks in respect to the molecular pathways contributing to learning. The goal of this proposal is to explore to which extent intron retention and excision is deployed in living animals and how it contributes to neuronal plasticity. First, I will use transcriptome-wide methods as well as single-molecule RNA visualization approaches to probe in vivo intron retention profiles and their regulation under physiological stimulation . Second, I will combine a targeted analysis of the public data from the recently updated Encode consortium, and the elaboration of minigene assays to identify the regulatory determinants of intron retention and excision . Ultimately, I will elaborate selective antisense oligonucleotides and apply them in living animals with high-precision surgical procedures to control intron patterns and explore the impact of intron regulation on neuron biology in mouse .
Selective mRNA Translation Control in Rodent Models Carrying Mutations in Genetic Autism Risk Factors Research Project | 1 Project MembersWith an estimate incidence of 1 in 100 children, autism spectrum disorders represent an enormous burden on the population. These developmental disorders develop in the first years of life and to date no mechanism-based treatments are available to the patients. One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. Recent work highlighted an unexpected convergence in pathophysiology between gene products contributing to seemingly distant cellular functions. Thus, findings from model organisms suggest that mutations in autism-associated synaptic components precipitate alterations in translational regulation which resemble dysfunctions emerging from direct genetic alterations in the mRNA translation machinery. Early work conceptualized translational de-regulation as representing "too high" or "too low" levels of translation. However, based on more recent evidence it is now hypothesized that alterations in translation machinery and cell signaling result in a selective translational de-regulation of specific mRNAs which are fundamental drivers of the pathophysiology of the disorders.
Endogenous RNA-based sensors for neuronal homeostasis and plasticity. Research Project | 1 Project MembersNeurons undergo profound plastic modifications but, at the same time, retain stable intrinsic properties. This implies sensing, signaling and homeostatic mechanisms that couple signaling to gene regulation. In this proposal I will examine a novel mechanism for transcriptional homeostasis in mammalian neurons. Specifically, I will test the hypothesis that the degradation of a class of intron-containing mRNAs contributes to a sensing mechanism that shapes the neuronal transcriptome. There is strong evidence of the link between mRNA decay factors in the cytoplasm and the regulation of gene transcription in the nuclei. Very recent discoveries link mutant mRNA decay by Nonsense Mediated Decay (NMD) with upregulation of the expression of genes with similar sequences, a process named Genetic Compensation (GC). One recently described class of endogenous transcripts destined for NMD arises from intron retention during alternative splicing . Roles for icRNA in nuclei and cytoplasm have been discovered, but most cytoplasmic icRNA are targeted by NMD, and their functional relevance remains a mystery. In analogy to the genetic compensation mechanism in mutant mRNAs, I hypothesize that degradation of endogenous cytoplasmic icRNAs triggers modifications of the neuronal transcriptome. Thus, cytoplasmic icRNAs would act as sensors for neuronal gene expression that signal the state of the cytosolic transcriptome and translatome back to the nucleus to achieve neuronal homeostasis. Using transgenic mouse lines, adenoviral-mediated knock-down and overexpression of reporter genes in cultured cortical neurons and RNA-Seq I will: (1) check whether GC works in post-mitotic neurons, (2) uncover endogenously degraded mRNA role in gene expression regulation.
Endogenous RNA-based sensors for neuronal homeostasis and plasticity. Research Project | 1 Project MembersImported from Grants Tool 4599654
