Stress is an out of the norm state caused by emotional or physical insults. While chronic stress is considered harmful, acute stress is thought to cause transient and reversible changes essential for fight or flight. Stress has been anecdotally associated with hair greying, but scientific evidence linking the two is scant. Here, using mouse stress models, we found that acute stress leads to hair greying through rapid depletion of melanocyte stem cells (MeSCs). Combining adrenalectomy, denervation, chemogenetics, cell ablation, and MeSC-specific adrenergic receptor knockout, we found that stress-induced MeSC loss is independent of the immune attack or adrenal hormones. Instead, hair greying results from activation of the sympathetic nervous system that innervates the MeSC niche. Upon stress, sympathetic nerve activation leads to burst release of the neurotransmitter norepinephrine, which acts directly on MeSCs. Norepinephrine drives quiescent MeSCs to proliferate rapidly, followed by migration and differentiation, leading to their permanent depletion from the niche. Transient suppression of MeSC proliferation with topical application of cell cycle inhibitors rescues stress-induced hair greying. Our studies demonstrate that stress-induced neuronal activity can be an upstream trigger that forces stem cells out of quiescence, and suggest that acute stress stimuli can be more detrimental than anticipated by causing rapid and irreversible loss of somatic stem cells.

SUMMARY Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207-phosphorylation provokes a new conformer of LysRS that inactivates its translational, but activates its transcriptional function. The crystal structure of an MSC sub-complex established that LysRS is held in the MSC by binding to the N-terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap4A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.

The mammalian NIMA-related kinases (Neks) are commonly referred to as mitotic kinases, although a definitive in vivo verification of this definition is largely missing. Reduction in the activity of Nek7 or its close paralog, Nek6, has previously been shown to arrest cells in mitosis, mainly at metaphase. In this study, we investigate the developmental and cellular roles of Nek7 kinase through the generation and analysis of Nek7-deficient mice. We show that absence of Nek7 leads to lethality in late embryogenesis or at early post-natal stages and to severe growth retardation. Mouse embryonic fibroblasts (MEFs) derived from Nek7 À/À embryos show increase tendency for chromosomal lagging, micronuclei formation and cytokinesis failure. Tetraploidy and aneuploidy were commonly observed and their prevalence arises with MEFs passages. The frequency of multicentrosomal cells in the mutant's MEF cells was higher, and it commonly occurred concurrently with a binuclear phenotype, suggesting cytokinesis failure etiology. Lastly, the percentage of mutant MEF cells bearing primary cilia (PC) was low, whereas a cell population having two cilia appeared in the mutant MEFs. Taken together, these results confirm Nek7 as a regulator of cell division, and reveal it as an essential component for mammalian growth and survival. The intimate connection between tetraploidy, aneuploidy and cancer development suggests that Nek7 deregulation can induce oncogenesis.

The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.