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Abstract

Lipids universally constitute biological membranes across the tree of life, yet the specific functions of distinct membrane lipid compositions are not clear.

Mammals synthesize thousands of chemically distinct lipids and maintain specialized lipidomes across various tissues. The brain requires specific lipid species to support membrane trafficking and neural function. This calls for a rewiring of the underlying lipid metabolic machinery during development, but when and how this occurs is unclear. To address this, I used mass spectrometry-based lipidomics to trace the establishment of the neural lipidome in both the developing mouse brain and in mouse embryonic stem cells differentiated into neurons in vitro. While orchestrated lipidome remodeling was observed across the embryonic and postnatal stages of brain development, neurons differentiated in vitro lacked remodeling and did not synthesize canonical neural lipids. Supplementing the cells with metabolic precursors of neural lipids prompted the synthesis of some but not all neural lipids, suggesting that both the availability of exogenous metabolic precursors and cell-intrinsic metabolic processes are limiting factors for the synthesis of neural lipids. Importantly, these results highlight the need to assess cells differentiated in vitro from a lipidomic perspective in order to inform differentiation procedures and generate cells that more closely resemble their in vivo counterparts.

It has been proposed that the unique lipid compositions of cellular membranes, such as those in neurons, serve to maintain mechanical properties critical to membrane function. In particular, cholesterol and lipid saturation are known to regulate membrane fluidity. As the plasma membrane is mechanically coupled to the active actomyosin cortex through membraneto- cortex linker proteins, I next investigated how the lipid compositionmediated fluidity of the plasma membrane affects the cortex. To this end, I perturbed cholesterol and lipid saturation in cultured mouse fibroblasts and found that lowering plasma membrane fluidity via either perturbation resulted in increased cortical tension and cell rounding. These findings suggest that membrane fluidity could be a potential regulator of cortical mechanics. Since the actomyosin cortex is a central regulator of cell shape and integrity, these findings highlight the importance of the homeostatic regulation of plasma membrane lipid composition, which constrains membrane fluidity to a narrow, favorable range in cells.