UNIverse - Public Research Portal
Profile Photo
Prof. Dr.
Patrick Tschopp
Department of Environmental Sciences
Profiles & Affiliations
Projects & Collaborations
11 found
Show per page
Project cover
Molecular crosstalk between muscles and motor neurons and its role in neuromuscular circuit assembly
Research Project  | 1 Project Members
Chronic or acute diseases affecting the neuromuscular system can cause debilitating symptoms in human patients, yet they may manifest through very different etiologies. For example, either muscle or nerve tissue can present the primary pathological phenotype. However, the intricate functional connection between the two tissues, through so-called neuromuscular circuits, will eventually result in deficiencies in both, if disease is allowed to progress unchecked. Correct embryonic assembly of these neuromuscular circuits is essential, in order to ensure faithful muscle-nerve communication. The required circuit specificity is determined - at least in part - by molecularly defined subgroups of motor neurons, so-called motor neuron «pools». Neurons of a given pool project their axons to a single muscle in the periphery. Whether or not distinct molecular subtypes also exist among the various muscle groups is currently less clear. We know, however, that both antero- and retrograde signals between muscle fibers and motor neurons play a crucial role in refining these circuits during development, and maintaining robustness and functionality during homeostasis. The goal of this proposal is thus to profile molecular signatures of circuit-specific muscle and motor neuron pairs, and to functionally test their relevance in neuromuscular circuit formation. For this, I propose to combine state-of-the-art single-cell RNA-sequencing of axon-backfilled motor neurons with bulk transcriptomic analyses of micro-dissected limb muscles connected to the corresponding motor neuron pools. Furthermore, we will exploit a unique experimental setting, in which one of the main motor nerve branches is re-routed and ectopically connects to a duplicated muscle, thereby shunting the original circuit logic. We will evaluate the role of emerging candidate genes using gain- and loss-of- function approaches in both muscle- and neuron-lineages. A better understanding of the molecular crosstalk between muscle and motor neurons will provide new insights into the mechanisms of neuromuscular circuit formation, refinement and maintenance, as well as support the development of regenerative therapies for treating human muscle and nerve diseases.
Project cover
Plasticity and molecular crosstalk between muscles and motor neurons in the developing limb neuromuscular system
Research Project  | 1 Project Members
Die kontrollierte Bewegung der Gliedmassen von Wirbeltieren beruht auf der Kontraktion peripherer Muskeln, welche durch Entscheidungsprozesse im zentralen Nervensystem gesteuert wird. Im Rückenmark leiten spezifische Gruppen von Motoneuronen diese Steuerungseingaben vom Gehirn an ihre entsprechenden Muskelziele weiter, und bilden zusammen mit sensorischen Neuronen hochspezifische neuromuskuläre Schaltkreise. Der korrekte Aufbau dieser Schaltkreise während der embryonalen Entwicklung ist essentiell, um später die richtigen Kontraktionsmuster der Muskeln und damit Bewegungskontrolle zu gewährleisten. Die erforderliche Spezifität dieser neuromuskulären Schaltkreise wird - zumindest teilweise - durch molekular definierte Untergruppen von Motoneuronen bestimmt, sogenannten Motoneuronen-«Pools». Neuronen eines bestimmten Pools innervieren immer nur einen einzelnen, spezifischen Muskel in der Peripherie. Dies geschieht durch wegleitende Signale, sogenannte 'axon guidance cues', welche die wachsenden Nervenstränge der molekular unterschiedlichen Motoneuronen-Pools in die Nähe ihrer jeweiligen Muskelziele lotsen. Ob unter den verschiedenen Muskelgruppen in der Peripherie auch molekulare Subtypen existieren oder nicht, ist derzeit noch unbekannt. Wir wissen jedoch, dass sowohl antero- wie auch retrograde Signale zwischen Muskelfasern und Motoneuronen eine entscheidende Rolle bei der Verfeinerung dieser Schaltkreise, deren Robustheit und deren Homöostase spielen. Ein besseres V erständnis der molekularen Wechselwirkungen in diesen Schaltkreisen wird uns daher neue Einblicke in die Ätiologie angeborener Fehlbildungen des neuromuskulären Systems der Extremitäten gewähren, sowie die Entwicklung von regenerativen Therapien für dieses Systems bei menschlichen Patienten unterstützen. Ziel des hier vorgeschlagenen Projektes ist es daher die Existenz unterschiedlicher molekularer Subtypen in den verschiedenen Muskelgruppen der Wirbeltiergliedmassen zu untersuchen, und sie mit den transkriptionellen Signaturen einzelner verbundener Motoneuronen zu integrieren. Basierend auf unseren eigenen Erkenntnissen in einem Modell der experimentell induzierten Polydaktylie, oder Vielfingerigkeit, gehe ich davon aus, dass die Ausbildung der Architektur dieser Schaltkreise eine erhebliche Plastizität aufweist - dies im Gegensatz zu dem, was man von der oben beschriebenen Logik erwarten würde. Bei einer durch Polydaktylie induzierten Verdoppelung des Muskels Flexor digiti quarti beobachten wir nämlich eine fehlgeleitete Nerv-zu-Muskel-V erbindung, außerhalb des normalerweise dafür vorgesehenen Schaltkreises. Wir werden diesen einzigartigen experimentellen Ansatz dazu benutzen, um die molekularen Wechselwirkungen von Motoneuronen und Muskeln innerhalb ihres normalen Schaltkreises zu untersuchen, wie auch nach dem Auftreten fehlgeleiteter Muskelkontakte. Durch die Analyse und Integration von Einzelzell-RNA-Sequenzieranalysen markierter Motoneuronen mit den molekularen Profilen der mit ihnen verbundenen Muskelgruppen, wollen wir Schlüsselregulatoren in dieser komplexen Wechselwirkung definieren, und deren Relevanz funktionell in vivo testen. Die Identifizierung molekularer Faktoren zur korrekten Bildung von Muskel- Nerv-Verbindungen wird unser Verständnis neuromuskulärer Schaltkreis-Architekturen verbessern, sowie die Entwicklung von therapeutischen Ansätzen zur Aufrechterhaltung ihrer motorischen Funktionen vorantreiben.
Project cover
Molecular evolution and ontogenetic development of dietary adaptations in vertebrates at the micro- and macro-evolutionary scale
Research Project  | 3 Project Members
Die Erschliessung neuer Nahrungsquellen - etwa durch Anpassungen in der Nahrungsaufnahme und -verwertung - spielt eine wichtige Rolle bei der Entstehung neuer Arten und trägt somit zum Erhalt der biologischen Vielfalt auf unserem Planeten bei. Im Rahmen unseres Sinergia Projektes untersuchen wir die damit einhergehenden morphologischen, physiologischen und genomischen Veränderungen im Verdauungssystem zweier artenreicher Wirbeltiergruppierungen, den Buntbarschen und den Säugetieren. Wir setzen dabei auf modernste Technologien im Bereich der vergleichenden und funktionellen Genomik sowie auf 3D-bildgebende Verfahren. Unser experimenteller Ansatz wird es uns erlauben, die zugrundeliegenden molekularen Vorgänge auf der Ebene einzelner Zellen des Verdauungstraktes zu untersuchen; zu testen, inwiefern diese Vorgänge flexibel auf unterschiedliche Nahrung reagieren; und die Ergebnisse mit der in der Evolution entstandenen Ernährungsformen der Arten - die sich in Fleisch- oder Pflanzenfresser, Generalisten oder Spezialisten aufteilen - in Beziehung zu setzen.
Project cover
Molecular evolution and ontogenetic development of dietary adaptations in vertebrates at the micro- and macro-evolutionary scale
Research Project  | 2 Project Members

Dietary adaptations — that is, all adaptations related to how nutrients are acquired and processed — play a central role in the evolution and maintenance of organismal diversity on Earth in general and in adaptive radiations of species in particular. In vertebrates, the trophic process can be divided into two fundamental components: food uptake and digestion. Through a timely combination of state-of-the-art genomics technologies and broad phylogenetic sampling, it is now possible to elucidate the molecular and developmental underpinnings of both feeding-related structures (e.g., jaws or teeth) and the digestive system at unprecedented resolution, as well as to evaluate their contributions to adaptation and diversification.

In the framework of this Sinergia proposal, we put forward an interdisciplinary and integrative approach, focusing our efforts towards a comprehensive understanding of dietary adaptations in the digestive system. Our multi-faceted approach is only possible through the joint expertise, research infrastructure, methodological skill-set, and biological samples of the consortium labs, thereby allowing each lab to expand substantially beyond their previous lines of research. Specifically, we propose a systematic and large-scale survey of dietary adaptations and their underlying morphological, cellular and gene regulatory changes across feeding strategies, key digestive organs (intestine and liver) and developmental stages in two prominent evolutionary radiations in vertebrates — of cichlid fishes from Lake Tanganyika and eutherian mammals — that cover both short (<6-9 million years, cichlids) and long (=75 million years, mammals) evolutionary time scales.

Our work plan is guided by a number of specific hypotheses. First, we hypothesize that digestive organ adaptations typically arise late in development, facilitated by decreased selective constraints. Second, while all major mutational types likely contributed to dietary adaptations in both cichlids and mammals, we conjecture that the predominant mutational mechanism is cis-regulatory changes in old genes in cichlids, as the short radiation time in this clade likely limited the accumulation of less rapidly accumulating coding mutations. Third, we predict that dietary novelties involved evolutionary changes in gene expression programs and the cellular composition of the digestive organs, and that all mutational types contributed to cell compositional changes. However, we surmise that new gene origination was key for the emergence of novel cell types, and that new cell types played a more prominent role for intestine than liver adaptations. Fourth, we hypothesize that the mechanisms and degree of phenotypic plasticity, leading to differences in intestine/liver anatomy and function, vary across development (i.e., more plasticity later in development) and between the two radiations (i.e., higher morphological plasticity in cichlids, but similar contributions of gene expression changes to phenotypic plasticity in cichlids and mammals). Finally, we note that our analyses of the unique and novel datasets generated in the proposed project will allow us to assess various general questions in an exploratory fashion, which will result in novel hypotheses to be tested in the future.

Our current predictions, research questions, and anticipated novel hypotheses, will be evaluated in the framework of four complementary goals. First, we will scrutinize the morphological features of the digestive system across development of representative cichlids using computed tomography scans and histological methods, which will set the stage for all subsequent molecular/cellular comparisons among cichlids and between cichlids and mammals. Second, we will generate and analyze extensive bulk and single-cell transcriptome data for the intestine and liver across development and adult stages of representative cichlids and mammals. We will thus trace evolutionary changes of gene expression programs and cellular compositions that underlie digestive organ innovations. Third, we will generate matched single-cell epigenomic datasets to explore the gene regulatory foundations of digestive organ development and adaptation. Finally, we will carry out dedicated feeding experiments in selected cichlids and a mammal (rat) to assess the extent to which adaptations may rapidly occur through phenotypic plasticity (i.e., developmental plasticity at the morphological, cellular, and molecular levels) rather than "hard-wired" genetic changes in the two vertebrate groups, respectively.

By contextualizing our anticipated results within the frameworks of dietary ecology and comparative digestive physiology, our work will substantially advance our understanding of the molecular, cellular and morphological evolution of dietary adaptations across different timescales and thus provide a novel and unique perspective on the evolution of vertebrates, including our own species.

Project cover
Elucidating the gene regulatory logic of convergent cell fate specification in the developing vertebrate skeleton
Research Project  | 1 Project Members
Cell fate specification - that is, how distinct cell types arise from a pool of precursor cells - is one of the hallmarks of embryonic development. During this process, a genome common to all cells of an organism is differentially interpreted at the gene regulatory level, to result in individualized cellular phenotypes. So far, most studies have focused on the specification of different cell types from a single progenitor pool. However, notable exceptions exist to this trajectory, such as in the vertebrate skeleton that, depending on anatomical location, develops from three distinct progenitor populations (neural crest, somitic and lateral plate mesoderm). Despite this diversity in embryonic origins and thesurrounding tissue environments, these three progenitor populations converge phenotypically to give rise to functionally equivalent skeletal cell types. With the current project, we aim to define the gene regulatory logic underlying such cell fate convergence. Specifically, we will decode how transcriptional networks assimilate differences in progenitor transcriptomes and tissue niches to produce analogous cell types from distinct embryonic sources. Based on preliminary data from our lab, I hypothesize that progenitor-specific transcription factor profiles, resulting from cell-intrinsic and -extrinsic differences in their embryonic origins, are integrated at the cis-regulatory level, via lineage-specific enhancer elements, to result in the transcriptional and phenotypic convergence of the three skeletal precursor pools. To functionally test these hypotheses, I propose to combine state-of-the-art functional genomics at single cell- and lineage-resolution with experimental embryology and targeted CRISPR/Cas9-genome modifications. Capitalizing on the superior temporal control in avian embryos, their ability to sustain transplantation experiments, and our expertise in developmental biology, molecular genetics and transcriptome analyses, we will: Define, at single cell- and lineage-resolution, the transcriptome and chromatin dynamics of the three progenitor pools, as they converge towards a common skeletal cell fate Elucidate the interplay of cell-intrinsic and cell-extrinsic parameters in this gene regulatory convergence using quail-chick grafts followed by single-cell RNA-sequencing and chromatin accessibility profiling Functionally validate candidate regulatory factors underlying this convergence in vivo, using the CRISPR/Cas9system in a lineage-specific manner in chicken embryos Collectively, our work will delineate the gene regulatory logic instructing the transcriptional and phenotypic convergence towards a common skeletal cell fate, across three distinct embryonic progenitor pools. As such, the project promises to define novel paradigms of cell fate specification control, for the skeletal system and beyond, and open new avenues applicable to regenerative medicine.
Project cover
A CRISPR/Cas9-screening platform to decipher conserved cell fate specification networks in vivo
Research Project  | 1 Project Members
The adult human body consists of hundreds, if not thousands, of distinct cell types. Examples include different neurons in the brain, epithelial cells lining the gut, or the cells that produce the bone or cartilage in our skeletons. During embryogenesis, all of these diverse cell types develop from a single progenitor cell - the fertilized egg. Understanding the different molecular mechanisms that orchestrate this diversification can help us re-create a particular cell type in a cell culture dish. Having access to such 'in vitro'-generated cells would then enable their use in tissue repair and replacement strategies in human patients. What are the potential difficulties in achieving these goals? Many cell type specification processes require complex interactions with the surrounding tissue. Hence, only in the context of a developing embryo can these processes be fully understood, making the use of non-human 'model organisms' indispensable. This, however, raises additional questions: how can we minimize the number of experimental animals used in these studies, and how can we ensure that findings in such model organisms also translate to us humans? To address these challenges, here I propose to integrate comparative genomics data to define conserved 'core regulatory switches' that specify a given cell type across species. We will then functionally test the relevance of these candidate 'switches' using genetic perturbations in chicken embryos. Our experimental approach will prevent the euthanasia of any pregnant female animal while at the same time maximize its relevance for the subsequent in vitro specification of human cell types.
Project cover
Seed funding - Convergent Cell Fate Decisions and Skeletal Patterning at Evolutionary, Embryonic and Single Cell Resolution
Research Project  | 1 Project Members
The concept of 'cell fate', central to both developmental biology and regenerative medicine, has seen dramatic shifts in recent years. Thanks to emerging single-cell technologies and cellular (re-)programming, we are now able to address questions resulting therefrom at unprecedented detail. While many studies have focused on the emergence of cellular diversity from a single precursor type, there are instances where distinct embryonic progenitor pools converge to give rise to functionally analogous cell types. What is the gene regulatory logic underlying such cell fate convergence? And how amenable are these transcriptional networks to evolutionary change, to result in distinct, species-specific morphologies? Here, I propose an integrative approach to elucidate this question using vertebrate skeletogenesis as a model system, over developmental and evolutionary timescales, at lineage- and single-cell resolution, during cell fate convergence and embryonic pattern formation. Building on my expertise in comparative transcriptomics and developmental biology, we will (1) study the gene regulatory logic of analogous cell fate specification from three distinct embryonic progenitor pools; (2) delineate the essential core regulatory nodes through a deep sampling of the vertebrate phylogeny and functionally test them via targeted in vitro specifications; and, ultimately, (3) integrate these insights to investigate species- specific and patterning-relevant in vivo cell fate decisions using single-cell RNA-sequencing and mathematical modeling. Collectively, our work will define core regulatory networks that specify a given skeletal cell fate across developmental and evolutionary levels, during cell fate convergence and embryonic patterning. As such, it will help to define novel paradigms of developmental cell fate decision control, for the skeletal system and beyond, and open new avenues for regenerative medicine.
Project cover
The role of muscle and motor neuron patterning in constraining digit number
Research Project  | 1 Project Members
During development, the musculoskeletal apparatus of the vertebrate limb integrates and patterns diverse tissue types with distinct embryonic origins. Namely, the bones of the appendicular skeleton originate from the lateral plate mesoderm, while the musculature and its innervating motor neurons derive from the somatic mesoderm and the neural tube, respectively. How is the patterning of such distinct embryonic progenitor populations coordinated, in order to give rise to a fully functional, moveable limb? Moreover, what are the potential developmental constraints originating from such patterning interdependency between different tissue types? We are studying the patterning of these three tissue types in vertebrate autopods, hands and feet, where the appendicular skeleton shows the highest degree of morphological diversity and functional specialization. We are using chicken experimental embryology as well as genetic mouse models (in collaboration with Rolf Zeller's group, Department of Biomedicine, Uni Basel) to address these questions.
Project cover
Cell fate decisions during digit development
Research Project  | 1 Project Members
The highest degree of morphological diversification, as well as functional specialization, of the vertebrate limb skeleton has occurred in its most distal part, the so-called autopod. Most of the diversity relates to the number of digits present, as well as the skeletal patterns of each individual digit. Each digit pattern is determined by the number and size of its bony elements, the phalanges, and how they are connected to each other via synovial joints. These configurations are specified by an embryonic sequence of inducing phalanx versus joint cell fates, as the individual digits are growing out during autopod development. Understanding how these phalanx versus joint cell fate decisions are made would thus allow us to decipher the underlying developmental mechanism of autopod morphological diversification. We are using experimental embryology, single-cell RNA-sequencing and bioinformatics to unravel the molecular aspects of these cell fate decisions. In collaboration with Dagmar Iber's group (D-BSSE ETH Zürich) we aim to develop in silico models of this patterning process, to better understand its evolutionary flexibility.