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Adult stem cells are responsible for life-long tissue maintenance. They reside in and interact with specialized tissue microenvironments (niches). Using murine hair follicle as a model, we show that when junctional perturbations in the niche disrupt barrier function, adjacent stem cells dramatically change their transcriptome independent of bacterial invasion and become capable of directly signaling to and recruiting immune cells. Additionally, these stem cells elevate cell cycle transcripts which reduce their quiescence threshold, enabling them to selectively proliferate within this microenvironment of immune distress cues. However, rather than mobilizing to fuel new tissue regeneration, these ectopically proliferative stem cells remain within their niche to contain the breach. Together, our findings expose a potential communication relay system that operates from the niche to the stem cells to the immune system and back. The repurposing of proliferation by these stem cells patch the breached barrier, stoke the immune response and restore niche integrity., eLife digest Most, if not all, tissues of an adult animal contain stem cells. These stem cells regenerate and repair damaged tissues and organs for the entire lifetime of an animal, contributing to a healthy life. They divide to make daughter cells that become either new stem cells or specialized cells of that organ. Adult stem cells exist in specific areas within tissues known as niches, where they interact with surrounding cells and molecules that inform their behavior. For example, cells and molecules within these niches can signal stem cells to remain in a ‘dormant’ state, but upon injury, they can mobilize stem cells to form new tissue and repair the wound. So far, it has been unclear how stem cells sense damage and stress and direct their efforts away from their normal duties towards repair. Here, Lay et al. studied the stem cells in the mouse skin that are responsible to regenerate hair. Every hair follicle contains a niche (the ‘bulge’), where these stem cells live and share their environment with cells that anchor the hair. The niche tethers to the stem cells through specific adhesion molecules that also help the niche to form a tight seal to prevent bacteria from entering. Lay et al. removed one of the adhesion molecules called E-cadherin, which caused a breach in the niche’s barrier. The stem cells sensed their damaged niche, prepared to multiply, and sent out stress signals to the immune system. The immune cells then arrived at the niche and sent signals back to the stem cells, prodding them to multiply and patch the barrier, while at the same time, keeping the inflammation in check. This remarkable ability of the stem cells to recruit immune cells and initiate a dialogue with them enabled the stem cells to divert their attention from regenerating hair and instead directing it towards the site of the tissue damage. Other stem cells, such as those in the lung or gut, may have similar mechanisms to detect and respond to physical damage. It will be interesting to investigate the underlying mechanism of how immune cells are involved in balancing stem cell regenerative capacity and response to physical damage. A better knowledge of these processes could help to regenerate tissues or even entire organs.

The neuronal RNA binding protein NOVA regulates splicing, shuttles to the cytoplasm, and co-localizes with target transcripts in dendrites, suggesting links between splicing and local translation. Here we identified >200 transcripts showing NOVA-dependent changes in abundance, but, surprisingly, HITS-CLIP revealed NOVA binds these RNAs in introns rather than 3′ UTRs. This led us to discover NOVA-regulated splicing of cryptic exons within these introns. These exons triggered nonsense mediated decay (NMD), as UPF1 and protein synthesis were required for NOVA's effect on RNA levels. Their regulation was dynamic and physiologically relevant. The NMD exons were regulated by seizures, which also induced changes in Nova subcellular localization and mediated large changes in synaptic proteins, including proteins implicated in familial epilepsy. Moreover, Nova haploinsufficient mice had spontaneous epilepsy. The data reveal a hidden means of dynamic RNA regulation linking electrical activity to splicing and protein output, and of mediating homeostatic excitation/inhibition balance in neurons. DOI: http://dx.doi.org/10.7554/eLife.00178.001, eLife digest After the DNA in a gene has been transcribed into messenger RNA, portions of the mRNA called introns are removed, and the remaining stretches of mRNA, which are known as exons, are spliced together. Within eukaryotic cells, a process known as alternative splicing allows a single gene to encode for multiple protein variants by ensuring that some exons are included in the final, modified mRNA, while other exons are excluded. This modified mRNA is then translated into proteins. Eukaryotic cells also contain proteins that bind to RNA to regulate alternative splicing. These RNA-binding proteins are often found in both the cytoplasm and nucleus of cells, and their involvement in splicing may be linked to other processes in the cell such as mRNA localization and translation. It has also become clear over the past two decades that certain types of RNA-binding proteins, including NOVA proteins, are only found in neurons, and that these proteins have been best characterized as alternative splicing regulators. Recent work has also suggested that they also have important roles in regulating neuronal activity and development, and that their actions in neuronal nuclei and cytoplasm might be coordinated. Now Eom et al. use the predictive power of a high throughput sequencing and crosslinking method termed HITS-CLIP to show that NOVA proteins can indirectly regulate cytoplasmic mRNA levels by regulating the process of alternative splicing in the nucleus to produce ‘cryptic’ exons in the brains of mice. The presence of these exons in the mRNA leads to the production of premature termination codons in the cytoplasm. These codons trigger a process called nonsense-mediated decay that involves identifying mRNA transcripts that contain nonsense mutations, and then degrading them. These cryptic exons were seen in mice missing the NOVA proteins, where they are expressed in abnormally high levels; in normal mice, these exons have not been seen before, hence they were termed ‘cryptic’. Eom et al. also show that these cryptic exons are physiologically relevant by inducing epileptic seizures in mice. Following the seizures, they find that the NOVA proteins up-regulate and down-regulate the levels of different cryptic exons, leading to changes in the levels of the proteins encoded by these mRNAs, including proteins that inhibit further seizures. Overall the results indicate that, by controlling the production of various proteins in neurons, these previously unknown cryptic exons have important roles in the workings of the brain. DOI: http://dx.doi.org/10.7554/eLife.00178.002