Osr1 is a common marker for distinct pre-adipogenic progenitors that mediates a myogenic to adipogenic fate transition

Abstract

Adipose depots arise at diverse anatomical locations, at different time points in development, and serve in part complementary functions. While white adipose tissue serves as energy storage, brown adipose tissue is able to dissipate energy to generate heat. This remarkable feature has raised hope for the treatment of metabolic disorders. However, despite extensive work has been done on the identification of brown pre-adipogenic progenitors in late embryogenesis and adult mice, their earliest origin is still obscure. This thesis combines latest techniques as single cell sequencing with classical approaches such as in vivo lineage tracing studies using the Osr1CreERt2/+;ROSAmTmG/+ mouse model to shed light on the very early steps of brown adipose tissue progenitor specification. By analyzing an early embryonic mesenchymal cell pool characterized by the expression of the transcription factor odd-skipped related 1 (Osr1), my work identified two distinct pre-adipogenic progenitor populations. At embryonic day (E)11.5, a pool of Osr1+ cells expressing EBF2 and PAX7 was revealed in the dermomyotome, in line with previous observations that brown adipose tissue traces back to this compartment. Importantly, this work for the first-time localized cells in the dermomyotome that gradually switch from a myogenic to a brown adipogenic identity. In addition, close inspection of OSR1 and adipogenic marker (PPARg/EBF2/DLK1) expression identified and localized the so far undetected first adipogenic founder population to the peritoneal wall close to the dermomyotome. Surprisingly, lineage tracing revealed brown adipogenic capacity in the embryo even before E11.5, earlier than previously demonstrated. This was traced back to a novel OSR1+ and PAX7-/EBF2- non-dermomyotomal source that I identified as meso-angioblast stem cells residing in the aorta-gonad-mesonephros (AGM) region. Loss of Osr1 resulted in a severe reduction of adipose tissue development, demonstrating functional involvement of Osr1 in adipogenesis. Further experiments revealed that Osr1 is required in vivo and sufficient in vitro to suppress the myogenic potential and promote adipogenesis. An interactome analysis suggested that during this process OSR1 cooperates with an array of epigenetic remodelers like MLL3, EP300, BRD4 as well as the pioneer TF of adipogenesis CEBPb, to prime and activate the adipogenic fate. In summary, this research introduces Osr1 as a common marker for two distinct pre-adipogenic progenitors in earliest development and demonstrates that Osr1 is necessary for a developmental lineage switch required for the establishment of adipose tissue.