Description of the thesis topic

Molecular and cellular mechanisms of neurosecretion: role of membrane asymmetry and scramblase-1 Protein

Neurons and neuroendocrine cells release neurotransmitters and hormones through regulated exocytosis. This secretory activity requires vesicle fusion with the plasma membrane. During secretion, membrane homeostasis and vesicle stock replenishment are ensured by a compensatory endocytosis mechanism, which allows the retrieval of membranes and proteins newly inserted via vesicular fusion. The coupling of exocytosis and endocytosis is essential for proper neurotransmission and hormone secretion. Our research team aims to decipher the molecular mechanisms regulating this coupling, as their dysfunction may contribute to the development of various nervous system disorders.

While research has primarily focused on the protein aspects of neurosecretion, the role of membrane phospholipids remains largely unexplored. Our team has pioneered this field and demonstrated that plasma membrane lipids are major regulators of vesicular trafficking. A key property of the plasma membrane lipid bilayer is the asymmetric distribution of phospholipids. We have shown, for the first time, that a transient disruption of this asymmetry is required for hormone secretion in neuroendocrine cells and for neurotransmission in some high-frequency synapses (Ory et al., Journal of Neuroscience, 2013; Caputo et al., Journal of Neuroscience, 2024). In parallel, we have demonstrated that Scramblase-1 (PLSCR1) activity disrupts plasma membrane asymmetry near vesicle fusion sites and regulates the recycling of secretory vesicles through compensatory endocytosis.

This discovery paves the way for an innovative PhD project aimed at deciphering the molecular and cellular mechanisms by which PLSCR1 controls neurosecretion and uncovering the link between phospholipid dynamics across membrane leaflets and the endocytosis process.

Our laboratory possesses PLSCR1 knockout mice. The experiments will be conducted on primary cultures of cerebellar neurons or neuroendocrine cells from the adrenal gland, utilizing a combination of cutting-edge techniques, including cell imaging (live cell video-microscopy, confocal, STED and electron microscopies, optogenetics), biochemistry (protein-protein interaction assays, immunoprecipitation, Bio-ID, western blot, next-generation lipid probes), and cellular and molecular biology (exocytosis and endocytosis assays, carbon fiber amperometry, transfection, viral infections, cloning).

Work Context

The doctoral student will work for a period of 36 months at the Institute of Cellular and Integrative Neuroscience (INCI – UPR3212), which is composed of 9 teams for a total of approximately 130 employees, including around fifty permanent researchers. The doctoral program will take place in the “Intracellular Membrane Traffic in Nervous and Neuroendocrine Systems” team, under the supervision of Dr. Stéphane Gasman. This team currently has approximately 15 people (including 6 permanent researchers). The CNRS is a leading research institute recognized worldwide for its scientific excellence. The doctoral student (M/F) will be enrolled in the Doctoral School of Life and Health Sciences at the University of Strasbourg (https://ed.vie-sante.unistra.fr).

Constraints and risks

no constraints