Mammalian color patterns are among the most recognizable characters found in nature and can have a profound impact on fitness. However, little is known about the mechanisms underlying their formation and subsequent evolution. Here we show that, in the African striped mouse (Rhabdomys pumilio), periodic dorsal stripes result from underlying differences in melanocyte maturation, which give rise to spatial variation in hair color, and we identify the transcription factor Alx3 as a regulator of this process. In embryonic dorsal skin, patterned expression of Alx3 foreshadows pigment stripes, and acts to directly repress Mitf, a master regulator of melanocyte differentiation, giving rise to light-colored hair. Moreover, Alx3 is also upregulated in the light stripes of chipmunks, which have independently evolved a similar pattern of dorsal stripes. Our results reveal a previously unappreciated mechanism for modulating spatial variation in hair color, and provide new insight into the ways in which phenotypic novelty evolves.

Implementation of regular physical activity helps in the maintenance of a healthy metabolic profile both in humans and mice through molecular mechanisms not yet completely defined. Here, we show that high-intensity interval training (HIIT) modifies the microRNA (miRNA) profile of circulating exosomes in mice, including significant increases inmiR-133aandmiR-133b. Importantly, treatment of sedentary mice with exosomes isolated from the plasma of trained mice improves glucose tolerance, insulin sensitivity, and decreases plasma levels of triglycerides. Moreover, exosomes isolated from the muscle of trained mice display similar changes in miRNA content, and their administration to sedentary mice reproduces the improvement of glucose tolerance. Exosomal miRNAs up-regulated by HIIT target insulin-regulated transcription factor forkhead box O1 (FoxO1) and, accordingly, expression ofFoxO1is decreased in the liver of trained and exosome-treated mice. Treatment with exosomes transfected with amiR-133bmimic or with a specific siRNA targetingFoxO1recapitulates the metabolic effects observed in trained mice. Overall, our data suggest that circulating exosomes released by the muscle carry a specific miRNA signature that is modified by exercise and induce expression changes in the liver that impact whole-body metabolic profile.