Abstract
Differentiation of neuronal cells is crucial for the development and function of the nervous system. This process involves high rates of membrane expansion, during which the synthesis of membrane lipids must be tightly regulated. In this work, using a variety of molecular and biochemical assays and approaches, including immunofluorescence microscopy and FRET analyses, we demonstrate that the proto-oncogene c-Fos (c-Fos) activates cytoplasmic lipid synthesis in the central nervous system and thereby supports neuronal differentiation. Specifically, in hippocampal primary cultures, blocking c-Fos expression or its activity impairs neuronal differentiation. When examining its subcellular localization, we found that c-Fos co-localizes with endoplasmic reticulum markers and strongly interacts with lipid-synthesizing enzymes, whose activities were markedly increased in vitro in the presence of recombinant c-Fos. Of note, the expression of c-Fos dominant-negative variants capable of blocking its lipid synthesis-activating activity impaired neuronal differentiation. Moreover, using an in utero electroporation model, we observed that neurons with blocked c-Fos expression or lacking its AP-1-independent activity fail to initiate cortical development. These results highlight the importance of c-Fos-mediated activation of lipid synthesis for proper nervous system development.
Highlights
Neuronal differentiation, an intricate cellular process, comprises a series of complex and coordinated events, such as cell proliferation, migration, and differentiation [1,2,3,4,5]
We evaluated whether c-Fos participates in the differentiation of rat hippocampal neurons
For a long time it was assumed that biosynthesis of most macromolecules in neurons was confined to the cell body [52, 53], an increasing body of molecular evidence has supported the presence of functional endoplasmic reticulum (ER)-resident components in axons [15,16,17, 54,55,56,57,58,59,60,61,62]
Summary
For a long time it was assumed that biosynthesis of most macromolecules in neurons was confined to the cell body [52, 53], an increasing body of molecular evidence has supported the presence of functional ER-resident components in axons [15,16,17, 54,55,56,57,58,59,60,61,62]. The effects of c-Fos on neuronal plasticity have always been linked to gene expression through its nuclear function, but given the evidence presented it is possible that they are associated with processes that involve changes in lipid homeostasis This can be visualized in the experiments carried out with dominant negative of the lipid synthesis activator function of c-Fos, where the same results of impairment on differentiation in culture are observed AP-1 activity should not be affected. This hypothesis can be extended to cortical development: when performing in utero experiments, the cells with no c-Fos expression remain at the ventricular and subventricular zones instead of migrating to the superior layers of the cortex, an observation that implies a strong failure in normal cortical development. Its lipid synthesis activator capacity might contribute to the high membrane expansion rates necessary for the extension of the different neuronal processes that favor polarization and the correct establishment of synaptic connections for normal nervous system function
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