Inflammation-induced mammalian target of rapamycin signaling is essential for retina regeneration.

Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation-induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia-derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin-28a, cell cycle-related genes and critical cytokines. Surprisingly, we identify microglia/macrophage-mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.

Sox11b regulates the migration and fate determination of Müller glia-derived progenitors during retina regeneration in zebrafish.

The transcription factor Sox11 plays important roles in retinal neurogenesis during vertebrate eye development. However, its function in retina regeneration remains elusive. Here we report that Sox11b, a zebrafish Sox11 homolog, regulates the migration and fate determination of Müller glia-derived progenitors (MGPCs) in an adult zebrafish model of mechanical retinal injury. Following a stab injury, the expression of Sox11b was induced in proliferating MGPCs in the retina. Sox11b knockdown did not affect MGPC formation at 4 days post-injury, although the nuclear morphology and subsequent radial migration of MGPCs were altered. At 7 days post-injury, Sox11b knockdown resulted in an increased proportion of MGPCs in the inner retina and a decreased proportion of MGPCs in the outer nuclear layer, compared with controls. Furthermore, Sox11b knockdown led to reduced photoreceptor regeneration, while it increased the numbers of newborn amacrines and retinal ganglion cells. Finally, quantitative polymerase chain reaction analysis revealed that Sox11b regulated the expression of Notch signaling components in the retina, and Notch inhibition partially recapitulated the Sox11b knockdown phenotype, indicating that Notch signaling functions downstream of Sox11b. Our findings imply that Sox11b plays key roles in MGPC migration and fate determination during retina regeneration in zebrafish, which may have critical implications for future explorations of retinal repair in mammals.

Lpar2b Controls Lateral Line Tissue Size by Regulating Yap1 Activity in Zebrafish.

LPA signaling plays important roles during cell migration and proliferation in normal and pathological conditions. However, its role during sensory organ development remains unknown. Here we show a LPA receptor Lpar2b is expressed in the posterior lateral line primordium (pLLP) and mechanosensory organs called neuromasts (NMs) in zebrafish embryos. Lpar2b loss-of-function significantly reduces the number of NMs and hair cells in the posterior lateral line (pLL). Further analysis reveals that Lpar2b regulates the patterning and tissue size of the pLLP. Interestingly, we show that knocking down a Hippo effector Yap1 phenocopies the result of Lpar2b depletion, and Lpar2b regulates the phosphorylation and activity of Yap1 in the pLLP. Importantly, a phosphorylation-resistant Yap1 rescues pLLP size and NM number in Lpar2b-depleted embryos. Our results indicate Lpar2b controls primordium size and NM number by regulating Yap1 activity in the lateral line system.

Game Theoretical Analysis on Cooperation Stability and Incentive Effectiveness in Community Networks.

Community networks, the distinguishing feature of which is membership admittance, appear on P2P networks, social networks, and conventional Web networks. Joining the network costs money, time or network bandwidth, but the individuals get access to special resources owned by the community in return. The prosperity and stability of the community are determined by both the policy of admittance and the attraction of the privileges gained by joining. However, some misbehaving users can get the dedicated resources with some illicit and low-cost approaches, which introduce instability into the community, a phenomenon that will destroy the membership policy. In this paper, we analyze on the stability using game theory on such a phenomenon. We propose a game-theoretical model of stability analysis in community networks and provide conditions for a stable community. We then extend the model to analyze the effectiveness of different incentive policies, which could be used when the community cannot maintain its members in certain situations. Then we verify those models through a simulation. Finally, we discuss several ways to promote community network's stability by adjusting the network's properties and give some proposal on the designs of these types of networks from the points of game theory and stability.