| Tyrosine phosphorylation is an important signaling mechanism in eukaryotic cells.Accumulating evidence indicates that the deregulated expression of members of the phosphatase of regenerating liver(PRL),subgroup of PTPs is linked to those tumor genesis and cancer metastasis related processes.However,the biological function of PRLs remain largely still unknown.In our study,we demonstrate that Drosophila homologues PRL-1,plays a critical role in central neural system and specifically regulate CO2 neural circuit in a neuroprotective way for maintenance of its normal physiological functions as stimulus response and neural signal transmission.The PRL-1 null mutants showed aging-progressive irreversible held-up wing posture,which could also be induced by treating with high-concentate of CO2.Ectopic overexrpression of PRL-1 in central nerve system(CNS)or blocking carbon-dioxide sensory receptor could rescue the abnormal wing phenotype perfectly.Further Calcium signaling experiment indicates that lost of PRL-1 could result in signal overload in certain antennal lobe region which implies that PRL-1 may act in a neuroprotective way in the central nerve system.Base on previous research we confirmed the interaction between PRL-1 and magnesium transportor Uex.The held-up wing phenotype also observed in neuronal knockdown Uex.Our further research prove that protein stability of Uex was regulated by PRL-1and Uex functions directly genetic downstream of PRL-1.It is the first time to provide evidence that Uex interacts with PRL-1 and form a complex to maintain its stability.The PRL-1/Uex complex is pointed out to take participate in protection of CO2 specific neural signaling transmission and odor responsive wing posture regulation.This may provide a new perspective to discover functions of PRLs and CNNMs(Uex)in mammalians.The functional integrity of central nerve system is the foundation of sensoring stimulus from environment.Which needs the intact development of original neural stem cells.In the central brain of Drosophila,the balance between neural stem cell,the neuroblast(NB)self-renewal and defferentiation via asymmetric division is critical for the maintenace of a healthy neural stem cell lifespan.There are researchs point out that the sophisticated temporal patterning regulation during neural development faces extrinsic stress such as inflammation,hypoxia,DNA damage stimulation could induce tumorigenesis by somatic cell reprogramming.Tumor originate from different cell have their own specificity,which malignant tumors tend to originate from precursors or stem cell during embryonic development stage,while tumors originate from somatic cells tend to be benign.We use high-dosage of X-Ray irradiation to mimic the external stimulus during development stage and tend to figure out how NBs regulate itself against tumorigenesis.We found that in Drosophila NBs,the DNA double-strand breaks(DSB)induced by the high-dosage of ionizing radiation lead to an early acccumulation of the transcription factor Prospero(Pros)in the nuclei of NBs in the 3rd instar larval brain.This nuclear Pros in turn terminates NB stem cell fate by a terminal symmetric division,causing the reduction of total NB numbers.Interestingly,we noticed that the elimination of a group of DNA double-strand break repair genes within homologous recombination(HR)repair pathway enhanced the early nuclear accumulation Pros.Combined with results from previous research in cell fate determinant Pros and its mammalian homologous Pros/PROX1.Our observations give us some enlightment that Pros may serve as a “monitor” of the effectiveness of DNA repair in NBs.When damaged DNA is beyond repair in such particular neural stem cell,Pros will acccumulates in the nucleus and terminates its stem cell fate,preventing potential malignant tumorogenesis.We are now investigating factor(s)that trigger early nulcear Pros accumulation in this process.This essay is seperated into two parts,the first part is to propose the protective function of PRL-1 against CO2 stimulus in central nerve system,which provided a new perspective for its functional research.Meanwhile,the research of neuroblasts DNA damage repair propose a new hypothesis for its mechanism of stemness maintanace under stress condition. |
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