Research Activity

Unraveling key regulators of developmental timing

Neuronal maturation is a growth process marked by the progressive acquisition of multiple distinct phenotypes. These include morphological changes in size and complexity, the acquisition of excitability and synaptic function and shifts in metabolism to support the growing energetic demand. Here, we aim to decipher a network of molecular pathways, including candidate epigenetic mechanisms, and the underlying regulatory logic that control the temporal acquisition of distinct neuronal maturation phenotypes. We will explore whether manipulation of this network can revert the maturation process or specific phenotypes and whether the combined manipulation of intrinsic and extrinsic, environmental regulators of maturation timing unlock late maturation stages in stem cells-based human model systems.

Understanding the coordination of maturation timing across CNS neuron types

The pace of brain developments displays substantial variation across species and within a given species across neuron types and brain regions. It takes almost two decades to build a fully functional cerebral cortex in humans. In contrast, neurons in the spinal cord and other regions mature at a much faster pace. By using region-specific hPSC differentiation assays we investigate the mechanisms that enable the coordination of maturation rates across neuron types. We will determine shared and unique molecular and functional maturation programs and temporal scaling factors across neuron types. The final goal is to identify upstream regulators responsible for their coordinated maturation and develop strategies to accelerate, delay and potential revert the maturation process in hPSC models.

Dissecting how disruption of neuronal maturation trajectories leads to disease.

The slow maturation of neurons in the human cerebral cortex is linked to the emergence of the unique properties of the human brain, including its complex cognitive abilities. However, its protracted developmental timeline makes the human brain particularly vulnerable to genetic and environmental insults that lead to pathological disfunctions of neuronal networks. Here, we aim to establish a novel experimental platform for disease modelling applications by combining advanced hPSC-based technologies to precisely control developmental stages and maturation timing in vitro and upon transplantation in the developing mouse brain in vivo. This platform will allow us to map the impact of disease risk factors onto maturation trajectories at high precision, test mechanisms of disease priming and convergence and dissect cell-type and stage-specific vulnerabilities.

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