Supervisor: Dr Valérie Wittamer
1st project:
Shaping the Brain’s Caretakers: Regulation of Microglial Function in Development
The zebrafish embryo provides a powerful vertebrate model to investigate microglia, the resident macrophages of the central nervous system (CNS), due to its optical transparency, rapid development, and genetic tractability. As in mammals, microglia in zebrafish originate from embryonic macrophages and require TGFβ signaling for their proper differentiation and the acquisition of a microglia-specific transcriptional identity. While this pathway is well established as a key determinant of microglial development, its broader contribution to microglial functional properties during early CNS development remains incompletely understood.
Microglia play essential roles in the developing brain, including the clearance of apoptotic neurons and the refinement of neural circuits through synaptic remodeling. Disruption of these functions has been implicated in a range of pathological contexts, such as neurodevelopmental disorders, inflammation, and neurodegeneration. As a result, there is growing interest in identifying the molecular pathways that regulate microglial activity in vivo, particularly those that could be targeted for therapeutic intervention.
This project aims to investigate the role of TGFβ-related signaling pathways in shaping microglial functional states during embryonic brain development. Using a combination of live imaging, multi-omic profiling, and in vivo CRISPR/Cas9-based genetic approaches, we will characterize microglial behavior and functional properties under conditions of altered TGFβ pathway activity. By leveraging existing and newly generated zebrafish mutant lines, this work will explore the contribution of individual components of the TGFβ superfamily to microglial physiology. Together, these studies will provide new insights into the molecular mechanisms that regulate microglial function in vivo and expand our understanding of how conserved signaling pathways influence neuro-immune interactions during development.
2nd project:
From Embryo to Adult: Species-Specific Strategies of Microglial Maintenance
The aim of this research is to provide new insights into the ontogeny and functional properties of microglia, the resident macrophages of the central nervous system (CNS). Microglia play essential roles in both physiological and pathological contexts and are increasingly recognized as important cellular targets in a wide range of neurological disorders, including neuroinflammation and neurodegeneration. A detailed understanding of how microglial populations are established, maintained, and regulated in the CNS is therefore of broad biological and clinical relevance.
Previous studies have profoundly reshaped the field by demonstrating that, in mice, microglia are maintained within the CNS throughout life independently of bone marrow-derived progenitors. These findings have highlighted the importance of local maintenance mechanisms in shaping microglial populations, while also raising new questions regarding the diversity and conservation of microglial ontogeny across vertebrates. In this context, zebrafish have emerged as a complementary model system to investigate microglial development and population dynamics in vivo.
Notably, our work has shown that microglia in zebrafish arise in two temporally distinct waves: an initial embryonic population that colonizes the developing brain, followed by a second population derived from larval hematopoietic stem cell-derived progenitors that contributes to the adult microglial pool. While this two-wave model establishes a framework for understanding microglial ontogeny in fish, the cellular dynamics and regulatory mechanisms underlying microglial maintenance and turnover across developmental stages remain incompletely understood.
To address these questions, this project will combine live imaging, fate mapping, microglial transplantation, single-cell profiling, and CRISPR/Cas9-based genetic approaches to characterize microglial populations of distinct developmental origins in the zebrafish brain. The resulting data will inform comparative transcriptomic analyses aimed at identifying conserved and species-specific molecular programs associated with microglial maintenance and function. Together, this work will contribute to a deeper understanding of how microglial populations are established and regulated in the vertebrate CNS.
3rd project:
Neuronal Regulation of Microglia during Vertebrate Development
Microglia are a distinct population of resident macrophages that act as immune sentinels and perform multiple roles in central nervous system (CNS) development, homeostasis, and disease. Beyond their immune functions, microglia are critical regulators of CNS development, and recent studies indicate that dysfunction in these cells can contribute directly to neurodevelopmental disorders, highlighting their therapeutic relevance. During development, microglia engage in complex interactions with neurons and other glial populations, yet the physiological outcomes of these cellular communications remain incompletely understood.
This project aims to investigate the bidirectional crosstalk between microglia and neurons in the developing brain, with a particular focus on how neuronal signals influence microglial behavior and function. Zebrafish provide a unique system to explore these questions, as their transparent embryos and tractable genetics allow in vivo observation and manipulation of microglia across developmental stages.
To address these questions, we will employ advanced techniques including confocal microscopy, transgenesis, CRISPR/Cas9 mutagenesis, chemo- and optogenetics, as well as comparative genomic and transcriptomic analyses. Together, these studies will provide new insights into the mechanisms by which neurons regulate microglial function during embryogenesis and will contribute to a deeper understanding of neuro-immune interactions in the developing CNS.