Beyond borders: Unveiling brain-periphery communication through the secretome

As a whole, the brain interstitial system (ISS) comprises 15-20% of brain tissue providing a supporting microenvironment that nurtures neuronal and glial cells. Many of the components that make up the brain extracellular fluid are not secreted locally at the brain, but rather synthesized in peripheral organs and then imported to the nervous system via the cerebrospinal fluid (CSF) or the bloodstream. Despite the relevance of the ISS during brain development, profiling the different molecules that compose the extracellular space of the brain has proven to be a daunting task due to the complexity of the sample involved and also the lack of specificity to isolate components in a tissue-specific fashion. By leveraging recent developments in proximity labeling techniques, we have started to explore the contribution of peripheral tissues to the brain extracellular milieu. To this end, we employ transgenic mice expressing a biotin ligase located at the inner surface of the endoplasmic reticulum to compile an in vivo secretome atlas across multiple tissues. So far, we have uncovered a large number of peripheral proteins that shape the composition and dynamics of this neglected component of the nervous system and its role in neurodevelopment in health and disease. Furthermore, this insight may serve as a unique entry point to identify new aspects of the pathophysiology of brain disorders, such as autism spectrum disorders (ASD).