Abstract
Gene expression and metabolism are coupled at numerous levels. Cells must sense and accurately respond to the nutrients in their environment, and specialized cells must synthesize the metabolic products required for their function. Pluripotent stem cells have the ability to differentiate into a wide variety of specialized cells. Exactly how metabolic state contributes to stem cell differentiation is the subject of intense investigation. Here, we show that the RNA‐binding activity of the stem cell translational regulator Musashi‐1 (MSI1) is allosterically inhibited by non‐esterified 18–22 carbon cis ω‐9 monounsaturated fatty acids. Inhibition is direct and highly specific. The fatty acid binds to the N‐terminal RNA Recognition Motif (RRM) and induces a conformational change that prevents RNA association. Musashi‐family proteins are critical for development of the brain, blood, and epithelial lineages, and play an important role in maintaining the viability of oligodendrocyte progenitor cells (OPCs). We identify stearoyl‐CoA desaturase 1 as a MSI1 target, revealing a feedback loop between ω‐9 fatty acid biosynthesis and MSI1 activity. We propose that other RRM proteins could act as metabolite sensors to couple gene expression changes to physiological state.
Highlights
The RNA-binding protein Musashi-1 (MSI1) is expressed in stem and progenitor cells of neural and epithelial lineage
Our data reveal that the long chain ω-9 fatty acids oleic acids between 18 and 22 carbons in length are allosteric inhibitors of MSI1 RNA binding activity
Our data show that stearoyl-CoA desaturase (SCD), the enzyme that catalyzes the ω-9 desaturation, is a MSI1 regulatory target
Summary
The RNA-binding protein Musashi-1 (MSI1) is expressed in stem and progenitor cells of neural and epithelial lineage. Analysis in mice and primary cells shows that MSI1 regulates neural development. Msi1−/− knockout mice are uncoordinated, ataxic, develop hydrocephaly, and die within 1–2 months after birth (Sakakibara et al, 2002). Their brains are small, contain an expansion of early lineage progenitor cells, and display fewer mature cell types than normal (Sakakibara et al, 2002). The phenotype and expression pattern reveal that MSI1 plays an early role in regulating neurogenesis and gliogenesis
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