Revealing the molecular underpinnings of mammalian body assembly

• Applicant: Aydan Bulut-Karslioglu, Ph.D.
• Subject Area: Developmental Biology ; General Genetics and Functional Genome Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 557054700

All mammals follow the same blueprint in the first days of life. In the days following fertilization of the egg, the cells multiply, begin to commit to different cell fates and form recognizable body axes in a process called gastrulation. Failure of implantation and gastrulation is the most common reason for pregnancy loss in mammals, and the underlying molecular mechanisms remain poorly understood. Cells in the developing embryo interface with maternal tissues as well as each other. The metabolic, signaling, and mechanical cues that cells receive from their immediate microenvironment shape developmental programs hand in hand with intrinsic genetic signals. Oxygen availability is one such parameter that affects the overall fitness of the embryo along with its developmental programs. Although early development almost entirely takes place in hypoxia, embryos and stem cells are cultured mostly under ambient oxygen in ex vivo cultures, impacting cellular energy metabolism, gene expression and differentiation programs. In the recent decade, stem cell-based models of embryos and tissues have been developed to study developmental events in greater detail. These models offer unique opportunities since they recapitulate developmental processes, can be generated in large numbers, allow various perturbations and time-resolved studies. Yet, recognizable limitations of gastrulation models prevent full recapitulation of the embryo at corresponding stages. We used hypoxia and a new cellular assembly strategy to generate a new stem cell-based embryo model, which successfully recapitulates the head-to-tail development of the early mouse embryo. This model, APassembloids, contains stage-appropriate anterior neural tissues that resemble early brain cells, together with all the posterior tissues that gastruloids/TLSs readily contain. This proposal uses this new model to address a major question that is only answerable under these controlled conditions: How does hypoxia shape brain development? What are the molecular mechanisms, and particularly the epigenetic and metabolic factors that integrate the hypoxia response into differentiation programs? We will use cutting-edge metabolomics and genomics to identify new molecular mechanisms that canalize hypoxia into gene expression programs guiding cell fate choices. These fresh perspectives will not only illuminate differentiation programs, but also offer a fresh perspective in understanding congenital diseases.

• DFG Programme: Research Grants