Laboratory of Regulatory Evolution

Research group of Patrick Tschopp

Understanding the origins of the phenotypic diversity in nature that surrounds us is a key question in biology. While selective forces drive this process at the population level, phenotypic diversity at the level of an individual is generated anew during embryonic development. The modification of developmental patterning processes, which can result in the variation of morphological features of an organism, thus provides the phenotypic substrate for natural selection to act upon.
Over the last three decades, advances in molecular biology and genomics have revealed surprisingly little variation in the genetic tool-kit that different organism have at their disposal to achieve this goal. Moreover, even distantly related species seem to use remarkably conserved gene cassettes for patterning during embryogenesis. So how is the astounding phenotypic diversity amongst various animal phyla generated, given such limited differences in the number and nature of their genes?

“Regulatory evolution”, i.e. changing when and where a particular gene is activated, has emerged as a powerful mechanism to drive the functional diversification of a limited gene repertoire. Evolving new gene expression patterns during development provides for a highly flexible and modular approach to morphological evolution, while avoiding pleiotropic effects usually associated with gene coding region mutations. Thanks to technological advances in sequencing technology, the molecular mechanisms of regulatory evolution can now be investigated in many species and tissue types, across different developmental stages.
We are taking advantage of these novel experimental approaches, to address fundamental questions in gene regulation and patterning during vertebrate embryogenesis. In particular, we are investigating how regulatory evolution is driving morphological diversification, while also trying to understand potential evolutionary and developmental constraints in this process. Moreover, we are interested in how cell fate decisions and complex tissue composition can affect the evolvability of organ patterning. To gain a better understanding of the underlying molecular and developmental mechanisms, we are focusing our efforts on the following three topics:

  1. What are the developmental and evolutionary constraints on gene regulation?
  2. How are cell specification and embryonic patterning intertwined?
  3. How does patterning of different tissue types constrain limb morphological evolution?

As a model system, we study the development of the vertebrate skeleton, and its associated neuromuscular system. The individual bones of the skeleton provide solid internal support for the general physical appearance of the highly diverse vertebrate bodyplans. At the same time, their flexible articulation, in conjunction with various attached muscle groups, forms the mechanical basis for different types of movements. Across vertebrate species, these skeletal elements and the associated musculature show tremendous variation in both size and shape, yet they all are generated from very similar cellular building blocks during embryogenesis. We are studying how cell differentiation and embryonic patterning can get modified on an evolutionary time-scale, using a variety of experimental approaches including comparative embryology, functional genomics, cell culture, bioinformatics and modeling.

Regulatory evolution of vertebrate skeletogenesis -
what are the developmental and evolutionary constraints on gene regulation?

Embryonic skeletogenesis occurs through the initial condensation of mesenchymal progenitors, followed by differentiation into the various skeletal cell types. These include chondrocytes, the bone-forming osteoblasts and joint progenitors that build the connections between mature skeletal elements. Depending on anatomical location, three distinct mesenchymal progenitor pools contribute to the different parts of the vertebrate skeleton: the somitic mesoderm forms the axial skeleton, whereas the lateral plate mesoderm and the neural crest give rise to the appendicular skeleton and parts of the cranial skeleton, respectively.
We are studying the gene regulatory mechanisms underlying the generation of these cell types, originating from distinct embryonic sources and in different species. We use next-generation sequencing techniques to interrogate the transcriptional output, chromatin state and transcription factor binding profiles of these cells during maturation, both in vivo and in vitro.

Cell fate decisions during digit development -
how are cell specification and embryonic patterning intertwined?

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.

Adapting the limb neuromuscular system to skeletal changes -
how does patterning of different tissue types constrain limb morphological evolution?

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.