Investigating intra- and inter-cellular mechanisms of cellular fate decision in olfactory sensory neurons

• Applicant: Antonio Scialdone, Ph.D.
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 448727785

Cells can adopt different, heritable fates in response to external signals and stochastic events during a process called cellular fate decision. This process is crucial during development in multicellular organisms and involves complex regulatory events both at the single- cell level and at the level of groups of interacting cells. This project aims to study cellular fate decision at both intra- and inter-cellular levels, by using the mouse olfactory system as a model. We will use a multidisciplinary approach based on bioinformatic and physical models, building on the results from previous work of the lab. We will follow an iterative procedure of model implementation, comparison with the data, formulation of predictions and experimental verification, in collaboration with the group of Dr. Luis Saraiva. In animals, the olfactory sensory system is fundamental for survival and reproduction. Most mammals have a complex olfactory system, with several organs and cell types. In particular, each of the cells responsible for odorant detection – the Olfactory Sensory Neurons (OSNs) – activates only one, randomly chosen olfactory receptor gene (OR) out of thousands, by means of a largely unknown mechanism, involving an intracellular re-arrangement of the chromatin spatial organization. Moreover, the activation probability for each OR depends on the region of the olfactory epithelium (OE) where the OSN sits, suggesting some level of intercellular coordination between different OSNs. We will build quantitative models for OR choice based on statistical physics, which can explain the key role of chromatin spatial organization in this process. Moreover, by exploiting a spatial transcriptomic dataset generated by the Saraiva lab, we will use computational methods to obtain, for the first time, a 3D map of gene expression patterns within the OE. This data will then be used to fit our model for OR choice to predict which parameters need to change in order to reproduce the spatial patterns of OR expression in the OE. In sum, this proposal uses complementary approaches that leverage the predictive power of quantitative models and the information provided by transcriptomic data, to shed light on cellular fate decision in the olfactory system. Such an interdisciplinary approach provides a framework that can be adopted to explore the interplay between intra- and inter-cellular mechanisms during cellular fate decision in other biological systems.

• DFG Programme: Research Grants