Biology subjects

Schweizer, M.

Publications and source records attributed to Schweizer, M..

29 records · Page 2Linked to original sources

bioRxiv2022

Abundant Phenotypic Parallelism, Incomplete Lineage Sorting, and Introgression in Open-Habitat Chats

Insights into the processes underpinning convergent evolution advance our understanding of the contributions of ancestral, introgressed, and novel genetic variation to phenotypic evolution. Phylogenomic analyses characterizing genome-wide gene tree heterogeneity can provide first clues about the extent of ILS and of introgression and thereby into the potential of these processes or (in their absence) the need to invoke novel mutations to underpin convergent evolution. Here, we were interested in understanding the processes involved in convergent evolution in open-habitat chats (wheatears of the genus Oenanthe and their relatives). To this end, based on whole-genome resequencing data from 50 taxa of 44 species, we established the species tree, characterized gene tree heterogeneity, and investigated the footprints of ILS and introgression within the latter. The species tree corroborates the pattern of abundant convergent evolution, especially in wheatears. The high levels of gene tree heterogeneity in wheatears are explained by ILS alone only for 30% of internal branches. For multiple branches with high gene tree heterogeneity, D-statistics and phylogenetic networks identified footprints of introgression. Finally, long branches without extensive ILS between clades sporting similar phenotypes provide suggestive evidence for a role of novel mutations in the evolution of these phenotypes. Together, our results suggest that convergent evolution in open-habitat chats involved diverse processes and highlight that phenotypic diversification is often complex and best depicted as a network of interacting lineages.

evolutionary biology↗

bioRxiv2022

Katanin is involved in Microtubule Polymerization into Dendritic Spines and regulates Synaptic Plasticity

Dynamic microtubules transiently polymerize into dendritic spines, however intracellular factors that regulate this process and their functional role at synapses are hardly understood. Using live imaging, electrophysiology, and glutamate uncaging, we show that the microtubule-severing complex katanin is located at individual spine synapses, participates in the activity-dependent process of microtubule polymerization into dendritic spines, and regulates synaptic plasticity. Overexpression of a dominant-negative ATPase-deficient katanin subunit, did not alter microtubule growth velocities or comet density in dendrites, but significantly reduced the activity-dependent invasion of microtubules into dendritic spines. Notably, functional inhibition of katanin significantly affected the potentiation of AMPA-receptor-mediated excitatory currents after chemical induction of long-term potentiation (cLTP). Furthermore, interference with katanin function prevented structural spine remodeling following single spine glutamate uncaging. Our data identify katanin at individual spine synapses in association with PSD-95. Thus, katanin regulates postsynaptic microtubules and modulates synaptic structure and function.

neuroscience↗

bioRxiv2022

KIF21B binds Myosin Va for Spine Entry and regulates Actin Dynamics to control Homeostatic Synaptic Downscaling

Homeostatic synaptic plasticity adjusts the strength of synapses to restrain neuronal activity within a physiological range. Postsynaptic GKAP controls the bidirectional synaptic scaling of AMPA receptors (AMPARs) however how chronic activity triggers postsynaptic protein remodeling to downscale synaptic transmission is barely understood. Here we report that the microtubule-dependent kinesin motor KIF21B interacts with GKAP and likewise enters dendritic spines in a myosin Va- and activity-dependent manner. We observed that under conditions of chronic activity KIF21B regulates actin dynamics in spines, triggers spine removal of GluA2-containing AMPA receptors, and mediates homeostatic synaptic downscaling of AMPA receptor-mediated mEPSC amplitudes. Our data highlight a myosin-kinesin interaction that enables the entry of the microtubule-dependent motor KIF21B into actin-rich spine compartments. A slow actin turnover rate might be beneficial for efficient protein removal from excitatory synapses, suggesting a functional role of KIF21B in a GKAP- and AMPA receptor-dependent mechanism, underlying homeostatic downscaling of neuronal firing.

neuroscience↗

bioRxiv2021

Ligands binding to the cellular prion protein induce its protective proteolytic release with therapeutic potential in neurodegenerative proteinopathies

The cellular prion protein (PrPC) is a central player in neurodegenerative diseases caused by protein misfolding, such as prion diseases or Alzheimers disease (AD). Expression levels of this GPI-anchored glycoprotein, especially at the neuronal cell surface, critically correlate with various pathomechanistic aspects underlying these diseases, such as templated misfolding (in prion diseases) and neurotoxicity and, hence, with disease progression and severity. In stark contrast to cell-associated PrPC, soluble extracellular forms or fragments of PrP are linked with neuroprotective effects, which is likely due to their ability to interfere with neurotoxic disease-associated protein conformers in the interstitial fluid. Fittingly, the endogenous proteolytic release of PrPC by the metalloprotease ADAM10 ( shedding) was characterized as a protective mechanism. Here, using a recently generated cleavage-site specific antibody, we shed new light on earlier studies by demonstrating that shed PrP (sPrP) negatively correlates with conformational conversion (in prion disease) and is markedly redistributed in murine brain in the presence of prion deposits or AD-associated amyloid plaques indicating a blocking and sequestrating activity. Importantly, we reveal that administration of certain PrP-directed antibodies and other ligands results in increased PrP shedding in cells and organotypic brain slice cultures. We also provide mechanistic and structural insight into this shedding-stimulating effect. In addition, we identified a striking exception to this, as one particular neuroprotective antibody, due to its special binding characteristics, did not cause increased shedding but rather strong surface clustering followed by fast endocytosis and degradation of PrPC. Both mechanisms may contribute to the beneficial action described for some PrP-directed antibodies/ligands and pave the way for new therapeutic strategies against devastating and currently incurable neurodegenerative diseases.

neuroscience↗

bioRxiv2020

Linked-read sequencing enables haplotype-resolved resequencing at population scale

The feasibility to sequence entire genomes of virtually any organism provides unprecedented insights into the evolutionary history of populations and species. Nevertheless, many population genomic inferences - including the quantification and dating of admixture, introgression and demographic events, and the inference of selective sweeps - are still limited by the lack of high-quality haplotype information. In this respect, the newest generation of sequencing technology now promises significant progress. To establish the feasibility of haplotype-resolved genome resequencing at population scale, we investigated properties of linked-read sequencing data of songbirds of the genus Oenanthe across a range of sequencing depths. Our results based on the comparison of downsampled (25x, 20x, 15x, 10x, 7x, and 5x) with high-coverage data (46-68x) of seven bird genomes suggest that phasing contiguities and accuracies adequate for most population genomic analyses can be reached already with moderate sequencing effort. At 15x coverage, phased haplotypes span about 90% of the genome assembly, with 50 and 90 percent of the phased sequence located in phase blocks longer than 1.25-4.6 Mb (N50) and 0.27-0.72 Mb (N90), respectively. Phasing accuracy reaches beyond 99% starting from 15x coverage. Higher coverages yielded higher contiguities (up to about 7 Mb/1Mb (N50/N90) at 25x coverage), but only marginally improved phasing accuracy. Finally, phasing contiguity improved with input DNA molecule length; thus, higher-quality DNA may help keeping sequencing costs at bay. In conclusion, even for organisms with gigabase-sized genomes like birds, linked-read sequencing at moderate depth opens an affordable avenue towards haplotype-resolved genome resequencing data at population scale.

evolutionary biology↗

bioRxiv2019

Regionally divergent drivers of historical diversification in the late Quaternary in a widely distributed generalist species, the common pheasant Phasianus colchicus

AimHistorical factors such as Pleistocene climate cycles and associated environmental changes have influenced the phylogeographic structure and demographic dynamics of many species. Resulting patterns not only depend on species life-history but also vary regionally. Consequently, different populations of species with large ranges over different biomes might have experienced divergent drivers of diversification and show different population histories. Such a representative species is the common pheasant Phasianus colchicus, an ecological generalist with a wide distribution in the Palearctic and at the edge of the Oriental region. We aimed at identifying distinct phylogeographic lineages of the common pheasant and investigating their evolutionary trajectories. Study locationAsia MethodsWe used coalescent approaches to describe the phylogeographic structure and to reconstruct the spatio-temporal diversification and demographic history of the common pheasant based on a comprehensive geographic sampling of 265 individuals genotyped at seven nuclear and two mitochondrial loci. ResultsThe common pheasant diversified during the late Pleistocene into eight distinct evolutionary lineages which only partly correspond to traditional morphological groups. It originated at the edge of the Qinghai-Tibetan plateau and spread from there to East and Central Asia. Only the widely distributed genetically uniform lowland lineage of East Asia showed a recent range and population expansion, starting during last glacial. More phylogeographic structure was found elsewhere with lineages showing no signs of recent range expansions. One lineage of subtropical south-central China this is the result of long-term isolation in a climatically stable and topographically complex region. In others from arid Central Asia and China, demographic and range expansions were impeded by repeated population fragmentation during dry glacial and recent aridification. Given such a phylogeographic structure and demographic scenarios among lineages, we proposed split the range-wide common pheasant into three species. Main conclusionsSpatio-temporal phylogeographic frameworks of widespread species complexes such as the common pheasant provide valuable opportunities to identify regionally divergent drivers of diversification.

evolutionary biology↗

bioRxiv2019

Unspecific expression in limited excitatory cell populations in interneuron-targeting Cre-driver lines can have large functional effects

1Transgenic Cre-recombinase expressing mouse lines are widely used to express fluorescent proteins and opto-/chemogenetic actuators, making them a cornerstone of modern neuroscience. Particularly, the investigation of interneurons has benefitted from the ability to target genetic constructs to defined cell types. However, the cell type specificity of some mouse lines has been called into questions. Here we show for the first time the functional consequences of unspecific expression in a somatostatin-Cre (SST-Cre) mouse line. We find large optogenetically evoked excitatory currents originating from unspecifically targeted CA3 pyramidal cells. We also used public Allen Brain Institute data to estimate expression specificity in other Cre lines. Another SST-Cre mouse lines shows comparable unspecificity, whereas a Parvalbumin-Cre mouse line shows much less unspecific expression. Finally, we make suggestions to ensure that the results from in-vivo use of Cre mouse lines are interpretable.

neuroscience↗

bioRxiv2019

Maintenance of cell type-specific connectivity and circuit function requires Tao kinase

Sensory circuits are typically established during early development, yet how circuit specificity and function are maintained during organismal growth has not been elucidated. To gain insight we quantitatively investigated synaptic growth and connectivity in the Drosophila nociceptive network during larval development. We show that connectivity between primary nociceptors and their downstream neurons scales with animal size. We further identified the conserved Ste20-like kinase Tao as a negative regulator of synaptic growth required for maintenance of circuit specificity and connectivity. Loss of Tao kinase resulted in exuberant postsynaptic specializations and aberrant connectivity during larval growth. Using functional imaging and behavioral analysis we show that loss of Tao-induced ectopic synapses with inappropriate partner neurons are functional and alter behavioral responses in a connection-specific manner. Our data show that fine-tuning of synaptic growth by Tao kinase is required for maintaining specificity and behavioral output of the neuronal network during animal growth.

neuroscience↗

bioRxiv2019

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

Amphisomes are transient organelles that derive from fusion of autophagosomes with late endosomes. They rapidly transform into degradative autolysosomes, whereas non-degradative roles of the autophagic pathway have been barely described. Here we show that in neurons BDNF/TrkB receptor bearing Rab7 / Light chain 3 (LC3) - positive amphisomes signal at presynaptic boutons during retrograde trafficking to the soma. Local signaling and inward transport essentially require the Rap GTPase-activating (RapGAP) protein SIPA1L2, which directly binds to TrkB and Snapin to connect TrkB-containing amphisomes to dynein. Association with LC3 regulates the RapGAP activity of SIPA1L2 and thereby retrograde trafficking. Following induction of presynaptic plasticity amphisomes dissociate from dynein at boutons, and this enables local signaling and promotes transmitter release. Accordingly, sipa1l2 knockout mice show impaired BDNF-dependent presynaptic plasticity. Collectively, the data suggest that TrkB-signaling endosomes are in fact amphisomes that during retrograde transport have local signaling capacity in the context of presynaptic plasticity.

neuroscience↗

bioRxiv2018

Visualization and regulation of translocons in Yersinia type III protein secretion machines during host cell infection

Type III secretion systems (T3SSs) are essential virulence factors of numerous bacterial pathogens. Upon host cell contact the T3SS machinery - also named injectisome - assembles a pore complex/translocon within host cell membranes that serves as an entry gate for the bacterial effectors. Whether and how translocons are physically connected to injectisome needles, whether their phenotype is related to the level of effector translocation and which target cell factors trigger their assembly have remained unclear. We employed the superresolution fluorescence microscopy techniques Stimulated Emission Depletion (STED) and Structured Illumination Microscopy (SIM) as well as immunogold electron microscopy to visualize Y. enterocolitica translocons during infection of different target cell types. Thereby we were able to resolve translocon and needle complex proteins within the same injectisomes and demonstrate that these fully assembled injectisomes are generated in a prevacuole, a PI(4,5)P2 enriched host cell compartment inaccessible to large extracellular proteins like antibodies. Furthermore, the putatively operable translocons were produced by the yersiniae to a much larger degree in macrophages (up to 25% of bacteria) than in HeLa cells (2% of bacteria). However, when the Rho GTPase Rac1 was activated in the HeLa cells, uptake of the yersiniae into the prevacuole, translocon formation and effector translocation were strongly enhanced reaching the same levels as in macrophages. Our findings indicate that operable T3SS translocons can be visualized as part of fully assembled injectisomes with superresolution fluorescence microscopy techniques. By using this technology we provide novel information about the spatiotemporal organisation of T3SS translocons and their regulation by host cell factors.\n\nAuthor SummaryMany human, animal and plant pathogenic bacteria employ a molecular machine termed injectisome to inject their toxins into host cells. Because injectisomes are crucial for these bacterias infectious potential they have been considered as targets for antiinfective drugs. Injectisomes are highly similar between the different bacterial pathogens and most of their overall structure is well established at the molecular level. However, only little information is available for a central part of the injectisome named the translocon. This pore-like assembly integrates into host cell membranes and thereby serves as an entry gate for the bacterial toxins. We used state of the art fluorescence microscopy to watch translocons of the diarrheagenic pathogen Yersinia enterocolitica during infection of human host cells. Thereby we could for the first time - with fluorescence microscopy - visualize translocons connected to other parts of the injectisome. Furthermore, because translocons mark functional injectisomes we could obtain evidence that injectisomes only become active when the bacteria are almost completely enclosed by host cells. These findings provide a novel view on the organisation and regulation of bacterial translocons and may thus open up new strategies to block the function of infectious bacteria.

microbiology↗

bioRxiv2016

Inference of evolutionary jumps in large phylogenies using Levy processes

While it is now widely accepted that the rate of phenotypic evolution may not necessarily be constant across large phylogenies, the frequency and phylogenetic position of periods of rapid evolution remain unclear. In his highly influential view of evolution, G. G. Simpson supposed that such evolutionary jumps occur when organisms transition into so called new adaptive zones, for instance after dispersal into a new geographic area, after rapid climatic changes, or following the appearance of an evolutionary novelty. Only recently, large, accurate and well calibrated phylogenies have become available that allow testing this hypothesis directly, yet inferring evolutionary jumps remains computationally very challenging. Here, we develop a computationally highly efficient algorithm to accurately infer the rate and strength of evolutionary jumps as well as their phylogenetic location. Following previous work we model evolutionary jumps as a compound process, but introduce a novel approach to sample jump configurations that does not require matrix inversions and thus naturally scales to large trees. We then make use of this development to infer evolutionary jumps in Anolis lizards and Loriini parrots where we find strong signal for such jumps at the basis of clades that transitioned into new adaptive zones, just as postulated by Simpson's hypothesis.

evolutionary biology↗