Mir-132/212 is required for maturation of binocular matching of orientation preference and depth perception

Mazziotti, Raffaele; Baroncelli, Laura; Ceglia, Nicholas; Chelini, Gabriele; Sala, Grazia Della; Magnan, Christophe; Napoli, Debora; Putignano, Elena; Silingardi, Davide; Tola, Jonida; Tognini, Paola; Arthur, J. Simon C.; Baldi, Pierre; Pizzorusso, Tommaso

doi:10.1038/ncomms15488

Cited by 34 publications

(34 citation statements)

References 71 publications

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“…To evaluate the role of Rbfox1 on visual function, the visual cliff test was used. The test evaluates the functional integrity of the retino-geniculo-cortical pathway by determining the depth perception of the animal [ 27 , 34 ]. The test is based on the animals’ innate tendency to avoid the deep side of the chamber.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of splicing regulator RBFOX1 compromises visual depth perception

Bok

et al. 2018

PLoS ONE

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Rbfox1 is a splicing regulator that has been associated with various neurological conditions such as autism spectrum disorder, mental retardation, epilepsy, attention-deficit/hyperactivity disorder and schizophrenia. We show that in adult rodent retinas, Rbfox1 is expressed in all types of retinal ganglion cells (RGCs) and in certain subsets of amacrine cells (ACs), within the inner nuclear (INL) and ganglion cell (GCL) layers. In the INL, all Rbfox1-positive cells were colocalized with GABAergic ACs, however not all GABAergic ACs were immunostained for Rbfox1. In the GCL, a vast majority of GABAergic dACs were Rbfox1-immunopositive. Furthermore, all cholinergic starburst ACs (SACs) in the INL (type a) and in the GCL (type b) were Rbfox1 positive. The expression of Rbfox1 in the retina significantly overlapped with expression of Rbfox2, another member of Rbfox family of proteins. Rbfox2, in addition to RGCs and ACs, was also expressed in horizontal cells. In developing retinas at E12 and E15, Rbfox1 is localized to the cytoplasm of differentiating RGCs and ACs. Between P0 and P5, Rbfox1 subcellular localization switched from cytoplasmic to predominantly nuclear. Downregulation of Rbfox1 in adult Rbfox1loxP/loxP mice had no detectable effect on retinal gross morphology. However, the visual cliff test revealed marked abnormalities of depth perception of these animals. RNA sequencing of retinal transcriptomes of control and Rbfox1 knockout animals identified a number of Rbfox1-regulated genes that are involved in establishing neuronal circuits and synaptic transmission, including Vamp1, Vamp2, Snap25, Trak2, and Slc1A7, suggesting the role of Rbfox1 in facilitating synaptic communications between ACs and RGCs.

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Section: Discussionmentioning

confidence: 99%

Downregulation of splicing regulator RBFOX1 compromises visual depth perception

Bok

et al. 2018

PLoS ONE

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“…Test was performed as previously described 76,77 with modifications. A transparent Plexiglas square arena (30 × 30 cm) was divided into two equal parts by aligning the middle of the arena with the edge of the table.…”

Section: Methodsmentioning

confidence: 99%

Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

et al. 2019

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Pericytes are positioned between brain capillary endothelial cells, astrocytes and neurons. They degenerate in multiple neurological disorders. However, their role in the pathogenesis of these disorders remains debatable. Here, we generated an inducible pericyte-specific Cre line and crossed pericyte-specific Cre mice with iDTR mice carrying Cre-dependent human diphtheria toxin receptor (DTR). After pericyte ablation with diphtheria toxin, mice developed an acute blood-brain barrier (BBB) breakdown, severe loss of blood flow, and a rapid neuron loss associated with loss of pericyte-derived pleiotrophin (PTN), a neurotrophic growth factor. Intracerebroventricular PTN infusions prevented neuron loss in pericyte-ablated mice despite persistent circulatory changes. Silencing pericyte-derived Ptn rendered neurons vulnerable to ischemic and excitotoxic injury. Our data demonstrate a rapid neurodegeneration cascade linking pericyte loss to acute circulatory collapse and loss of PTN neurotrophic support. These findings could have implications for the pathogenesis and treatment of neurological disorders associated with pericyte loss and/or neurovascular dysfunction.

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“…Because previous studies suggested that miR-132 made an important contribution to neuronal function and maturation, 14 , 15 , 21 , 25 we conducted therapeutic trials to see what would happen to HD mice if miR-132 were supplied to the HD brains. To compensate for the shortage of miR-132 in HD brains, we constructed a viral miR-132- expression system using recombinant adeno-associated viruses (rAAVs).…”

Section: Resultsmentioning

confidence: 99%

Supplemental Treatment for Huntington’s Disease with miR-132 that Is Deficient in Huntington’s Disease Brain

Fukuoka

Takahashi

Fujita

et al. 2018

Molecular Therapy - Nucleic Acids

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Huntington’s disease (HD) is an intractable neurodegenerative disorder caused by mutant Huntingtin (HTT) proteins that adversely affect various biomolecules and genes. MicroRNAs (miRNAs), which are functional small non-coding RNAs, are also affected by mutant HTT proteins. Here, we show amelioration in motor function and lifespan of HD-model mice, R6/2 mice, by supplying miR-132 to HD brains using a recombinant adeno-associated virus (rAAV) miRNA expression system. miR-132 is an miRNA related to neuronal maturation and function, but the level of miR-132 in the brain of R6/2 mice was significantly lower than that of wild-type mice. Our miR-132 supplemental treatment, i.e., supplying miR-132 to the brain, produced symptomatic improvement or retarded disease progression in R6/2 mice; interestingly, it had little effect on disease-causing mutant HTT mRNA expression and its products. Therefore, the findings suggest that there may be a therapeutic way to treat HD without inhibiting and/or repairing disease-causing HTT genes and gene products. Although miR-132 supplement may not be a definitive treatment for HD, it may become a therapeutic method for relieving HD symptoms and delaying HD progression.

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Mir-132/212 is required for maturation of binocular matching of orientation preference and depth perception

Cited by 34 publications

References 71 publications

Downregulation of splicing regulator RBFOX1 compromises visual depth perception

Downregulation of splicing regulator RBFOX1 compromises visual depth perception

Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

Supplemental Treatment for Huntington’s Disease with miR-132 that Is Deficient in Huntington’s Disease Brain

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