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The secretome mouse provides a genetic platform to delineate tissue-specific in vivo secretion

Significance Serum is a complex mixture of proteins that originate from a wide range of cells and tissues. At present, it is impossible to know what set of proteins any given tissue contributes to the circulating proteome. Here, we describe a genetic model called the secretome mouse. We show this transgenic mouse, which employs proximity biotinylation, provides a robust strategy for delineating the tissue-specific secretome. We demonstrate the utility of the secretome mouse by identifying the set of in vivo proteins secreted by endothelial cells as well as by skeletal muscle with and without exercise. This genetic strategy should, therefore, be useful in delineating a wide range of in vivo physiology and for the rational development of disease-relevant biomarkers. At present, it remains difficult to deconvolute serum in order to identify the cell or tissue origin of a given circulating protein. Here, by exploiting the properties of proximity biotinylation, we describe a mouse model that enables the elucidation of the in vivo tissue-specific secretome. As an example, we demonstrate how we can readily identify in vivo endothelial-specific secretion as well as how this model allows for the characterization of muscle-derived serum proteins that either increase or decrease with exercise. This genetic platform should, therefore, be of wide utility in understanding normal and disease physiology and for the rational design of tissue-specific disease biomarkers.