title: miR-285-Yki/Mask double-negative feedback loop mediates blood-brain barrier integrity inDrosophila.
abstract: The Hippo signaling pathway is highly conserved fromDrosophilato mammals and plays a central role in maintaining organ size and tissue homeostasis. The blood-brain barrier (BBB) physiologically isolates the brain from circulating blood or the hemolymph system, and its integrity is strictly maintained to perform sophisticated neuronal functions. Until now, the underlying mechanisms of subperineurial glia (SPG) growth and BBB maintenance during development are not clear. Here, we report anmiR-285-Yorkie (Yki)/Multiple Ankyrin repeats Single KH domain (Mask) double-negative feedback loop that regulates SPG growth and BBB integrity. Flies with a loss ofmiR-285have a defective BBB with increased SPG ploidy and disruptive septate junctions. Mechanistically,miR-285directly targets the Yki cofactor Mask to suppress Yki activity and down-regulates the expression of its downstream targetcyclin E, a key regulator of cell cycle. Disturbance ofcyclin Eexpression in SPG causes abnormal endoreplication, which leads to aberrant DNA ploidy and defective septate junctions. Moreover, the expression ofmiR-285is increased by knockdown ofykiormaskand is decreased withykioverexpression, thus forming a double-negative feedback loop. This regulatory loop is crucial for sustaining an appropriate Yki/Mask activity andcyclin Elevel to maintain SPG ploidy and BBB integrity. Perturbation of this signaling loop, either by dysregulatedmiR-285expression or Yki activity, causes irregular SPG ploidy and BBB disruption. Furthermore, ectopic expression ofmiR-285promotes canonical Hippo pathway-mediated apoptosis independent of the p53 or JNK pathway. Collectively, these results reveal an exquisite regulatory mechanism for BBB maintenance through anmiR-285-Yki/Mask regulatory circuit.
authors.affiliation: Department of Biological Sciences, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Biological Sciences, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Chunli
authors.initials: C
authors.lastname: Pei
authors.affiliation: The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China.
authors.forename: Linqing
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Oral Basic Science, College of Stomatology, Dalian Medical University, Dalian 116044, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xiao
authors.affiliation: Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China.
authors.forename: Songshu
authors.initials: S
authors.lastname: Meng
authors.affiliation: The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing 100850, China; bixl@dmu.edu.cn zyuan620@yahoo.com.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Zengqiang
authors.initials: Z
authors.lastname: Yuan
authors.affiliation: Department of Biological Sciences, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China; bixl@dmu.edu.cn zyuan620@yahoo.com.|Institute of Cancer Stem Cell, Cancer Center, Dalian Medical University, Dalian 116044, China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Bi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002453:Cell Cycle; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011003:Ploidies; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D000091102:YAP-Signaling Proteins; D000099317:Hippo Kinases
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D015534:Trans-Activators; D000091102:YAP-Signaling Proteins; C000627093:MIRN285 microRNA, Drosophila; C582878:Mask protein, Drosophila; C503814:Yki protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
keywords: Hippo; Mask; blood–brain barrier; miR-285; subperineurial glia