|Last Name:||Tuoc||Position:||Wissenschaftlicher Mitarbeiter|
|Akademischer Titel:||Dr. rer. nat.||Tel.:||+49-(0)551/39-7082|
1994-1998: Undergraduate study at Natural Science College of Hanoi National University, Vietnam.
2001-2003: Graduate study at University of Hannover, Germany.
2004-2007: Postgraduate study at Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
1998-2001: Research staff at Institute of Biotechnology, Vietnam Academy of Science and Technology, Vietnam.
2002-2003: Graduate Research Assistant at Institute of Developmental and Applied physiology, University of Hannover, Germany.
2004-2007: Graduate Research Assistant at Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (Supervisor: Prof. Anastassia Stoykova).
2008-2013: Postdoctoral fellow at Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (Supervisor: Prof. Anastassia Stoykova).
4.2013-present: Research group leader at Institute of Neuroanatomy, University medical Göttingen (UMG), Germany (Director: Prof. Dr. Jochen F. Staiger).
Awarded Scholarships & Support
DAAD, DFG, Max Planck Society, EMBO, University Medical Center Göttingen (UMG), DFG Center for Nanoscale Microscopy & Molecular Physiology of the Brain (CNMPB)
mSWI/SNF (BAF) complexes are indispensable for the neurogenesis and development of embryonic olfactory epithelium.
Bachmann C*, Nguyen H*, Rosenbusch J*, Pham L, Rabe T, Patwa M, Sokpor G, Seong RH, Ashery-Padan R, Mansouri A, Stoykova A, Staiger JF, Tuoc T..
Plos Genetics, 2016. 12(9), *equally contributed authors
Neurogenesis is a key developmental event through which neurons are generated from neural stem/progenitor cells. Chromatin remodeling BAF (mSWI/SNF) complexes have been reported to play essential roles in the neurogenesis of the central nervous system. However, whether BAF complexes are required for neuron generation in the olfactory system is unknown. Here, we identified onscBAF and ornBAF complexes, which are specifically present in olfactory neural stem cells (oNSCs) and olfactory receptor neurons (ORNs), respectively. We demonstrated that BAF155 subunit is highly expressed in both oNSCs and ORNs, whereas high expression of BAF170 subunit is observed only in ORNs. We report that conditional deletion of BAF155, a core subunit in both onscBAF and ornBAF complexes, causes impaired proliferation of oNSCs as well as defective maturation and axonogenesis of ORNs in the developing olfactory epithelium (OE), while the high expression of BAF170 is important for maturation of ORNs. Interestingly, in the absence of BAF complexes in BAF155/BAF170 double-conditional knockout mice (dcKO), OE is not specified. Mechanistically, BAF complex is required for normal activation of Pax6-dependent transcriptional activity in stem cells/progenitors of the OE. Our findings unveil a novel mechanism mediated by the mSWI/SNF complex in OE neurogenesis and development.
Ablation of BAF170 in Developing and Postnatal Dentate Gyrus Affects Neural Stem Cell Proliferation, Differentiation, and Learning.
Tuoc T, Dere E, Radyushkin K, Pham L, Nguyen H, Tonchev AB, Sun G, Ronnenberg A, Shi Y, Staiger JF, Ehrenreich H, Stoykova A.
Molecular Neurobiology, 2016. doi:10.1007/s12035-016-9948-5
The BAF chromatin remodeling complex plays an essential role in brain development. However its function in postnatal neurogenesis in hippocampus is still unknown. Here, we show that in postnatal dentate gyrus (DG), the BAF170 subunit of the complex is expressed in radial glial-like (RGL) progenitors and in cell types involved in subsequent steps of adult neurogenesis including mature astrocytes. Conditional deletion of BAF170 during cortical late neurogenesis as well as during adult brain neurogenesis depletes the pool of RGL cells in DG, and promotes terminal astrocyte differentiation. These derangements are accompanied by distinct behavioral deficits, as reflected by an impaired accuracy of place responding in the Morris water maze test, during both hidden platform as well as reversal learning. Inducible deletion of BAF170 in DG during adult brain neurogenesis resulted in mild spatial learning deficits, having a more pronounced effect on spatial learning during the reversal test. These findings demonstrate involvement of BAF170-dependent chromatin remodeling in hippocampal neurogenesis and cognition and suggest a specific role of adult neurogenesis in DG in adaptive behavior.
Zbtb20 modulates the sequential generation of neuronal layers in developing cortex.
Tonchev AB, Tuoc T, Rosenthal EH, Studer M, Stoykova A.
Molecular Brain, 2016. doi: 10.1186/s13041-016-0242-2.
During corticogenesis, genetic programs encoded in progenitor cells at different developmental stages and inherited in postmitotic neurons specify distinct layer and area identities. Transcription factor Zbtb20 has been shown to play a role for hippocampal development but whether it is implicated in mammalian neocortical morphogenesis remains unknown.
Here, we report that during embyogenesis transcription factor Zbtb20 has a dynamic spatio-temporal expression pattern in mitotic cortical progenitors through which it modulates the sequential generation of cortical neuronal layer identities. Zbtb20 knock out mice exhibited enhanced populations of early born L6-L4 neuronal subtypes and a dramatic reduction of the late born L3/L2 neurons. This defect was due to a temporal misbalance in the production of earlier versus later born neurons, leading to a progressive diminishing of the progenitor pool for the generation of L3-L2 neurons. Zbtb20 implements these temporal effects in part by binding to promoter of the orphan nuclear receptor CoupTF1/Nr2f1. In addition to its effects exerted in cortical progenitors, the postmitotic expression of Zbtb20 in L3/L2 neurons starting at birth may contribute to their proper differentiation and migration.
Our findings reveal Zbtb20 as a novel temporal regulator for the generation of layer-specific neuronal identities.
Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development.
Nguyen H*, Sokpor G*, Pham L, Rosenbusch J, Stoykova A, Staiger JF, Tuoc T.
Cell Cycle, 2016. 2016, 18;15(10):1317-24, equally contributed authors
The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.
Loss of BAF (mSWI/SNF) complexes causes global transcriptional and chromatin state changes in forebrain development.
Ramanathan Narayanan, Mehdi Pirouz, Cemil Kerimoglu, Linh Pham, Robin J. Wagener, Kamila A. Kiszka, Joachim Rosenbusch, Michael Kessel, Andre Fischer, Anastassia Stoykova, Jochen F. Staiger, and Tran Tuoc.
Cell Reports, 2015. 13, 1–13
BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knock-out (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and down-regulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3, UTX) and potentiate their activity. Importantly BAF complexes are indispensable for forebrain development, including proliferation, differentiation and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls global transcriptional program and chromatin state in development.
ATP-dependent BAF chromatin remodeling complexes play an essential role in the maintenance of the gene expression program by regulating the structure of chromatin. There is increasing evidence that BAF complexes based on the alternative ATPase subunits, Brg1 and Brm, control the differentiation of neural stem cells (NSCs) to generate distinct neural cell types and modulate trans-differentiation between cell types. The BAF complexes have dedicated functions at different stages of neural differentiation that appear to arise by combinatorial assembly of their subunits. Furthermore, the differentiation of NSCs is regulated by the tight interactions between the BAF chromatin remodeling complex and the transcriptional machinery. Here, we review recent insights into the functional interaction between BAF complexes and various transcription factors (TFs) in neural differentiation and cellular reprogramming
The mammalian neocortex is a sheet of cells covering the cerebrum that provides the structural basis for the perception of sensory inputs, motor output responses, cognitive function, and mental capacity of primates. Recent discoveries promote the concept that increased cortical surface size and thickness in phylogenetically advanced species is a result of an increased generation of neurons, a process that underlie higher cognitive and intellectual performance in higher primates and humans. Here, we review some of the advances in the field, focusing on the diversity of neocortical progenitors in different species, and cellular mechanisms of neurogenesis. We discuss recent views on intrinsic and extrinsic molecular determinants, including the role of epigenetic chromatin modifiers and microRNA, in the control of neuronal output in developing cortex and in the establishment of normal cortical architecture.
The multi-subunit chromatin remodeling BAF complex controls different developmental processes. Using cortex-specific conditional knockout and overexpression mouse models, we have recently reported that BAF170, a subunit of the vertebrate BAF chromatin remodeling complex, interacts with transcription factor (TF) Pax6 to control cortical size and volume. The mechanistic basis includes suppression of the expression of Pax6 target genes, which are required for genesis of cortical intermediate progenitors (IPs) and specification of late neuronal subtype identity. In addition, we showed that a dynamic competition between BAF170 and BAF155 subunits within the BAF complex during progression of neurogenesis is a primary event in modulating the size of the mammalian cortex. Here, we present additional insights into the interaction between the BAF complex and TF Pax6 in the genesis of IPs of the developing cortex. Furthermore, we show that such competition between BAF170 and BAF155 is involved as well in the determination of the size of the embryonic body. Our results add new insights into a cell-intrinsic mechanism, mediated by the chromatin remodeling BAF complex, that controls vertebrate body shape and size.
Chromatin regulation by BAF170 controls cerebral cortical size and thickness.
Tuoc TC, Boretius S, Sansom NS, Pitulescu ME, Frahm, J, Livesey FJ, Stoykova A.
Developmental Cell, 2013. 25 , 1–14
Increased cortical size is essential to the enhanced intellectual capacity of primates during mammalian evolution. The mechanisms that control cortical size are largely unknown. Here, we show that mammalian BAF170, a subunit of the chromatin remodeling complex mSWI/SNF, is an intrinsic factor that controls cortical size. We find that conditional deletion of BAF170promotes indirect neurogenesis by increasing the pool of intermediate progenitors (IPs) and results in an enlarged cortex, whereas cortex-specific BAF170 over-expression results the opposite phenotype. Mechanistically, BAF170 competes with BAF155 subunit in the BAF complex, affecting euchromatin structure and thereby modulating the binding efficiency of the Pax6/REST-corepressor complex to Pax6 target genes that regulate the generation of IPs and late cortical progenitors. Our findings reveal a molecular mechanism mediated by the mSWI/SNF chromatin-remodeling complex that controls cortical architecture.
The ubiquitin-proteosome system (UPS) is a non-lysosomal proteolysis system involved in the degradation of irrelevant/misfolded intracellular proteins. The protein substrates of this system are tagged by ubiquitin in sequential reactions that target them for proteasome-dependent destruction. In the developing central nervous system, ubiquitin-mediated proteolysis has recently emerged as an important player in the regulation of neural progenitor proliferation, cell specification, neuronal differentiation, maturation, and migration. E3 ubiquitin ligases are crucial components in the UPS because they provide the specificity that determines which substrates are targeted for ubiquitin-dependent proteolysis. In this review, we discuss the molecular mechanisms of the UPS, focusing primarily on the roles of E3 ligases and their substrates in sequential steps of neurogenesis.
Selective cortical layering abnormalities and behavioral deficits in cortex-specific Pax6 knock-out mice.
Tuoc TC*, Radyushkin K*, Tonchev AB, Pinon MC, Ashery-Padan R, Molnar Z, Davidoff MS, Stoykova A.
J Neurosci, 2009. 29(26):8335-8349
The transcription factor Pax6 has been implicated in neocortical neurogenesis in vertebrates, including humans. Analyses of the role of Pax6 in layer formation and cognitive abilities have been hampered by perinatal lethality of Pax6 mutants. Here, we generated viable mutants exhibiting timed, restricted inactivation of Pax6 during early and late cortical neurogenesis using Emx1-Cre and hGFAP-Cre lines, respectively. The disruption of Pax6 at the onset of neurogenesis using Emx1-Cre line resulted in premature cell cycle exit of early progenitors, increase of early born neuronal subsets located in the marginal zone and lower layers, and a nearly complete absence of upper layer neurons, especially in the rostral cortex. Furthermore, progenitors, which accumulated in the enlarged germinal neuroepithelium at the pallial/subpallial border in the Pax6 mutants, produced an excess of oligodendrocytes. The inactivation of Pax6 after generation of the lower neuronal layers using hGFAP-Cre line did not affect specification or numbers of late-born neurons, indicating that the severe reduction of upper layer neurons in Pax6 deficiency is mostly attributable to a depletion of the progenitor pool, available for late neurogenesis. We further show that Pax6(fl/fl);Emx1-Cre mutants exhibited deficiencies in sensorimotor information integration, and both hippocampus-dependent short-term and neocortex-dependent long-term memory recall. Because a majority of the morphological and behavior disabilities of the Pax6 mutant mice parallel abnormalities reported for aniridia patients, a condition caused by PAX6 haploinsufficiency, the Pax6 conditional mutant mice generated here represent a valuable genetic tool to understand how the developmental cortical disruption can lead to a human behavior abnormality.
Altered molecular regionalization and normal thalamocortical connections in cortex-specific Pax6 knock-out mice.
Pinon MC*, Tuoc TC*, Ashery-Padan R, Molnar Z, Stoykova A.
J Neurosci, 2008. 28(35):8724-8734.
Transcription factor Pax6 exerts a prominent rostrolateral(high) to caudomedial(low) expression gradient in the cortical progenitors and have been implicated in regulation of area identity in the mammalian cortex. Herein, we analyzed the role of Pax6 in molecular arealization and development of thalamocortical connections in the juvenile cortex-specific conditional Pax6 knock-out mice (Pax6cKO). Using a set of molecular markers of positional identity (Id2, Cadherin6, COUP-TF1, RZRbeta, and EphA7), we show that, in the juvenile Pax6cKO, the relative size of caudal cortical areas (putative visual and somatosensory) are mildly enlarged, whereas the rostral domain (putative motor) is severely reduced. Despite the rostral shift of graded expression of areal markers, the distribution of area-specific thalamocortical and corticofugal projections appear normal in the Pax6cKO. This indicates that change of the size of cortical areas is not accompanied by a change in cortical identity. We show furthermore that, despite a severe depletion of supragranular cortical layers and accumulation of cells along the pallial-subpallial boundary, thalamocortical fibers establish a periphery-related pattern of the somatosensory cortex in normal position in Pax6cKO. Our findings indicate that Pax6 expression gradients in cortical progenitors do not directly impart thalamocortical or corticofugal areal identity.
The transcription factor Pax6 is an important developmental regulator. Spatiotemporal control of Pax6 expression during embryogenesis is crucial for regulating distinct aspects of cortical development. Here, we report that Trim11, a member of the TRIM/RBCC protein family of E3 ubiquitin ligases, interacts with Pax6 and mediates Pax6 degradation via the ubiquitin-proteasome system. Trim11 overexpression decreases endogenous Pax6 protein levels and represses Pax6 functions, including Pax6-dependent transactivation and neurogenesis. Abrogation of endogenous Trim11 expression in the developing cortex increases the level of insoluble forms of Pax6 and enhances apoptosis. We provide evidence that the B30.2 domain of Trim11 is essential for the clearance of insoluble cell proteins. Furthermore, we show that the expression of Trim11 is directly regulated by Pax6 in developing cortex in vivo. Our findings indicate that an autoregulatory feedback loop between Trim11 and Pax6 maintains a balance between the levels of Pax6 and Trim11 proteins in cortical progenitors, having an essential role for the Pax6-dependent neurogenesis.
Although the transcription factor Pax6 plays an essential role in neurogenesis, layer formation and arealization in the developing mammalian cortex, the mechanisms by which it accomplishes these regulatory functions are largely unknown. Pax6 and the ETS family transcription factor Er81, which is presumed to play a role in the specification of a sublineage of layer 5 projection neurons, are expressed with a prominent rostrolateral-high to caudomedial-low gradient in cortical progenitors. In the absence of functional Pax6, progenitors do not express Er81 and the rostrolateral cortex lacks Er81-positive layer 5 neurons. In this study, we investigated the transcriptional regulation of Er81 and provide evidence that Er81 is a direct target of Pax6.
We identified and analyzed the regulatory function of an evolutionarily conserved upstream DNA sequence in the putative mouse Er81 promoter. Three potential Pax6 binding sites were identified in this region. We found that the presence of one of these sites is necessary and sufficient for full activation of the Er81 promoter in Pax6-transfected HeLa cells, while other still unknown factors appear to contribute to Er81 promoter activity in cortical progenitors and neuronal cells. The results suggest that endogenous Pax6, which is expressed at the highest level in progenitors of the rostrolateral cortex, exerts region-specific control of Er81 activity, thus specifying a subpopulation of layer 5 projection neurons.
We conclude that the genetic interplay between the transcription factors, Pax6 and Er81, is responsible, in part, for the regional specification of a distinct sublineage of layer 5 projection neurons.
Conditional activation of Pax6 in the developing cortex of transgenic mice causes progenitor apoptosis.
Berger J, Berger S, Tuoc TC, D'Amelio M, Cecconi F, Gorski JA, Jones KR, Gruss P, Stoykova A.
Development, 2007. 134(7):1311-1322.
During development, Pax6 is expressed in a rostrolateral-high to caudomedial-low gradient in the majority of the cortical radial glial progenitors and endows them with neurogenic properties. Using a Cre/loxP-based approach, we studied the effect of conditional activation of two Pax6 isoforms, Pax6 and Pax6-5a, on the corticogenesis of transgenic mice. We found that activation of either Pax6 or Pax6-5a inhibits progenitor proliferation in the developing cortex. Upon activation of transgenic Pax6, specific progenitor pools with distinct endogenous Pax6 expression levels at different developmental stages show defects in cell cycle progression and in the acquisition of apoptotic or neuronal cell fate. The results provide new evidence for the complex role of Pax6 in mammalian corticogenesis.