Papers by R. jeroen Pasterkamp
<b>Copyright information:</b>Taken from "Expression patterns of and during rat n... more <b>Copyright information:</b>Taken from "Expression patterns of and during rat neural development suggest roles in axon guidance and neuronal migration"http://www.biomedcentral.com/1471-213X/7/98BMC Developmental Biology 2007;7():98-98.Published online 29 Aug 2007PMCID:PMC2008261.coronal sections of the adult meso-diencephalic dopamine (mdDA) system. A, C and E show consecutive sections of the rostral part of mdDA system, B, D and F of its caudal part. Dorsal is to the top. (A, B) labels mdDA neurons in the subtantia nigra (SN) and ventral tegmental area (VTA). Arrows in A through F outline the position of the SN as visualized by TH labeling. Arrowheads in B, D and F indicate the central part of the VTA. (A-F) Note that whereas overlap in and expression is largely confined to the lateral aspect of the SN (C, D), and predominantly overlap in the central part of the VTA (F, indicated by arrowhead). No expression is detected in the SN (E, F). Asterisk indicates the fasciculus retroflexus. (G, H) Colocalization of TH protein (brown) and (G; purple) in the SN and of TH protein (brown) and (H; purple) in the VTA reveals or -positive mdDA neurons (red arrows in G, H), mdDA neurons that lack these transcripts (arrowheads in G, H), and non-mdDA neurons or cells that express or (black arrows in G, H). 7A, Sema7A; C1, plexinC1; fr, fasciculus retroflexus; mt, mammillothalamic tract; pc, pars compacta; pr, pars reticulare. Scale bar 250 μm (A-F), and 65 μm (G, H).
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Expression patterns of semaphorin7A and plexinC1 during rat neural development suggest roles in a... more Expression patterns of semaphorin7A and plexinC1 during rat neural development suggest roles in axon guidance and neuronal migration
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Nature methods, Jan 10, 2017
The actin cytoskeleton is essential for many fundamental biological processes, but tools for dire... more The actin cytoskeleton is essential for many fundamental biological processes, but tools for directly manipulating actin dynamics are limited to cell-permeable drugs that preclude single-cell perturbations. Here we describe DeActs, genetically encoded actin-modifying polypeptides, which effectively induce actin disassembly in eukaryotic cells. We demonstrate that DeActs are universal tools for studying the actin cytoskeleton in single cells in culture, tissues, and multicellular organisms including various neurodevelopmental model systems.
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Nature communications, Mar 21, 2017
We have previously shown higher-than-expected rates of schizophrenia in relatives of patients wit... more We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05-21.6; P=1 × 10(-4)) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10(-7)). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08-1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel ...
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The Lancet. Neurology, 2016
Temporal lobe epilepsy is a common and frequently intractable seizure disorder. Its pathogenesis ... more Temporal lobe epilepsy is a common and frequently intractable seizure disorder. Its pathogenesis is thought to involve large-scale alterations to the expression of genes controlling neurotransmitter signalling, ion channels, synaptic structure, neuronal death, gliosis, and inflammation. Identification of mechanisms coordinating gene networks in patients with temporal lobe epilepsy will help to identify novel therapeutic targets and biomarkers. MicroRNAs (miRNAs) are a family of small non-coding RNAs that control the expression levels of multiple proteins by decreasing mRNA stability and translation, and could therefore be key regulatory mechanisms and therapeutic targets in epilepsy. In the past 5 years, studies have found changes in miRNA levels in the hippocampus of patients with temporal lobe epilepsy and in neural tissues from animal models of epilepsy. Early functional studies showed that silencing of brain-specific miR-134 using antisense oligonucleotides (antagomirs) had pote...
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Advances in Experimental Medicine and Biology, 2009
Meso-diencephalic dopamine neurons (mdDA) neurons are located in the retrorubral field (RRF), sub... more Meso-diencephalic dopamine neurons (mdDA) neurons are located in the retrorubral field (RRF), substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) and give rise to prominent ascending axon projections. These so-called mesotelencephalic projections are organized into three main pathways: the mesostriatal, mesocortical and mesolimbic pathways. Mesotelencephalic pathways in the adult nervous system have been studied in much detail as a result of their important physiological functions and their implication in psychiatric, neurological and neurodegenerative disease. In comparison, relatively little is known about the formation of these projection systems during embryonic and postnatal development. However, understanding the formation of mdDA neurons and their projections is essential for the design of effective therapies for mdDA neuron-associated neurological and neurodegenerative disorders. Here we summarize our current knowledge of the ontogeny of mdDA axon projections in subsystems of the developing rodent central nervous system (CNS) and discuss the cellular and molecular mechanisms that mediate mdDA axon guidance in these CNS regions.
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Encyclopedia of Life Sciences, 2002
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Human Molecular Genetics, 2013
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Acta Neuropathologica Communications, 2019
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Acta Neuropathologica, 2019
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FEBS Journal, 2020
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M ICALs (for A/blecule /nteracting with CasL) form a recently discovered family of evolutionary c... more M ICALs (for A/blecule /nteracting with CasL) form a recently discovered family of evolutionary conserved signal transduction proteins. They contain multiple well-conserved domains known for interactions with the cytoskeleton, cytoskeletal adaptor proteins, and other signaling proteins. In addition to their ability to bind other proteins, MICALs contain a large NADPH-dependent flavoprotein monooxygenase enzymatic domain. Although MICALs have already been implicated in a variety of cellular processes, their function during axonal pathfinding in the Drosophila neuromuscular system has been best characterized. During the establishment of neuromuscular connectivity in the fruit fly, MICAL binds the axon guidance receptor Plexin A and transduces semaphorin-la-mediated repiJsive axon guidance. Intriguingly, mutagenesis and pharmacological inhibitor studies suggest a role for MICAL flavoenzyme redox functions in semaphorin/plexin-mediated axonal pathfinding events. This review summarizes o...
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Following the decline of neurogenesis at birth, progenitors of the subventricular zone (SVZ) rema... more Following the decline of neurogenesis at birth, progenitors of the subventricular zone (SVZ) remain mostly in a quiescent state in the adult human brain. The mechanisms that regulate this quiescent state are still unclear. Here, we isolated CD271+ progenitors from the aged human SVZ for single-cell RNA sequencing analysis. Our transcriptome data revealed the identity of progenitors of the aged human SVZ as late oligodendrocyte progenitor cells. We identified the Wnt pathway antagonist SFRP1 as a possible signal that promotes quiescence of progenitors from the aged human SVZ. Administration of WAY-316606, a small molecule that inhibits SFRP1 function, stimulates activation of neural stem cells both in vitro and in vivo under homeostatic conditions. Our data unravel a possible mechanism through which progenitors of the adult human SVZ are maintained in a quiescent state and a potential target for stimulating progenitors to re-activate.
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Current Biology
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Journal of Neurochemistry
Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease affectin... more Amyotrophic lateral sclerosis (ALS) is a fatal and progressive neurodegenerative disease affecting upper and lower motor neurons with no cure available. Clinical and animal studies reveal that the neuromuscular junction (NMJ), a synaptic connection between motor neurons and skeletal muscle fibers, is highly vulnerable in ALS and suggest that NMJ defects may occur at the early stages of the disease. However, mechanistic insight into how NMJ dysfunction relates to the onset and progression of ALS is incomplete, which hampers therapy development. This is, in part, caused by a lack of robust in vitro models. The ability to combine microfluidic and induced pluripotent stem cell (iPSC) technologies has opened up new avenues for studying molecular and cellular ALS phenotypes in vitro. Microfluidic devices offer several advantages over traditional culture approaches when modeling the NMJ, such as the spatial separation of different cell types and increased control over the cellular microenvironment. Moreover, they are compatible with 3D cell culture, which enhances NMJ functionality and maturity. Here, we review how microfluidic technology is currently being employed to develop more reliable in vitro NMJ models. To validate and phenotype such models, various morphological and functional read‐outs have been developed. We describe and discuss the relevance of these read‐outs and specifically illustrate how these read‐outs have enhanced our understanding of NMJ pathology in ALS. Finally, we share our view on potential future directions and challenges.
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Nature Communications
Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite... more Midbrain dopaminergic (DA) axons make long longitudinal projections towards the striatum. Despite the importance of DA striatal innervation, processes involved in establishment of DA axonal connectivity remain largely unknown. Here we demonstrate a striatal-specific requirement of transcriptional regulator Nolz1 in establishing DA circuitry formation. DA projections are misguided and fail to innervate the striatum in both constitutive and striatal-specific Nolz1 mutant embryos. The lack of striatal Nolz1 expression results in nigral to pallidal lineage conversion of striatal projection neuron subtypes. This lineage switch alters the composition of secreted factors influencing DA axonal tract formation and renders the striatum non-permissive for dopaminergic and other forebrain tracts. Furthermore, transcriptomic analysis of wild-type and Nolz1−/− mutant striatal tissue led to the identification of several secreted factors that underlie the observed guidance defects and proteins that...
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The EMBO Journal
Semaphorin ligands interact with plexin receptors to contribute to functions in the development o... more Semaphorin ligands interact with plexin receptors to contribute to functions in the development of myriad tissues including neurite guidance and synaptic organisation within the nervous system. Cell‐attached semaphorins interact in trans with plexins on opposing cells, but also in cis on the same cell. The interplay between trans and cis interactions is crucial for the regulated development of complex neural circuitry, but the underlying molecular mechanisms are uncharacterised. We have discovered a distinct mode of interaction through which the Drosophila semaphorin Sema1b and mouse Sema6A mediate binding in cis to their cognate plexin receptors. Our high‐resolution structural, biophysical and in vitro analyses demonstrate that monomeric semaphorins can mediate a distinctive plexin binding mode. These findings suggest the interplay between monomeric vs dimeric states has a hereto unappreciated role in semaphorin biology, providing a mechanism by which Sema6s may balance cis and trans functionalities.
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Brain Communications
Increasingly, repeat expansions are being identified as part of the complex genetic architecture ... more Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11,700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 x 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosop...
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Papers by R. jeroen Pasterkamp