Rac1 impairs retinal axon degeneration via Kif2a in a mouse model of chronic ocular hypertension
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ABSTRACT:
PROVIDER: PRJNA1040182 | ENA |
REPOSITORIES: ENA
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Project description:Rac1, a member of the small G protein Rho family, has been implicated in neurodegenerative diseases. However, its role in axon degeneration is not fully understood. Here we found that activation of Rac1 exacerbated axonal transport damage in an experimental glaucoma model. Inhibiting Rac1 activity by genetic or pharmacological methods alleviated the dysfunction of axonal transport and improved the integrity of microtubule by upregulating the expression of β-III tubulin and myelin basic protein. Rac1 interacted with Sirt1, a key molecule of Wallerian degeneration, which regulated the activity of PAK1, a downstream molecule of Rac1. Furthermore, Rac1 modulated Kif motors at the transcriptional level, among which Kif2a, a lysosome-location regulator, was negatively regulated by Rac1. Intravitreal injection of Kif2a siRNA reversed the improvement of Rac1 inhibition-mediated axonal transport through reducing autophagolysosomes. Our results suggest that Rac1/Kif2a accelerates the process of RGC axon degeneration by impairing the autophagic flux in glaucoma, which may be an intriguing therapy target for glaucoma.
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Project description:Canonical Wnt signaling plays critical roles in development and tissue renewal by regulating β-catenin target genes. Recent evidence showed that β-catenin-independent Wnt signaling is also required for faithful execution of mitosis. This mitotic Wnt signaling functions through Wnt-dependent stabilization of proteins (Wnt/STOP), as well as through components of the LRP6 signalosome. However, the targets and specific functions of mitotic Wnt signaling still remain uncharacterized. Using phosphoproteomics, we identified that Wnt signaling regulates the microtubule depolymerase KIF2A during mitosis. We found that Dishevelled recruits KIF2A via its N-terminal and motor domains, which is further promoted upon LRP6 signalosome formation during mitosis. We show that Wnt signaling modulates KIF2A interaction with PLK1, which is critical for KIF2A localization and the assembly of a bipolar mitotic spindle. Accordingly, Wnt signaling promotes chromosome congression during metaphase by monitoring KIF2A protein levels at the spindle poles both in somatic cells and in pluripotent stem cells. Our findings highlight a novel function of Wnt signaling during cell division, which could have important implications for genome maintenance, notably in stem cells.
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Project description:In the developing spinal cord, Sonic hedgehog (Shh) attracts commissural axons toward the floor plate. How Shh regulates the cytoskeletal remodeling that underlies growth cone turning is unknown. We found that Shh-mediated growth cone turning requires the activity of Docks, which are unconventional GEFs. Knockdown of Dock3 and 4, or their binding partner ELMO1 and 2, abolished commissural axon attraction by Shh in vitro. Dock3/4 and ELMO1/2 were also required for correct commissural axon guidance in vivo. Polarized Dock activity was sufficient to induce axon turning, indicating that Docks are instructive for axon guidance. Mechanistically, we show that Dock and ELMO interact with Boc, the Shh receptor, and that this interaction is reduced upon Shh stimulation. Furthermore, Shh stimulation translocates ELMO to the growth cone periphery and activates Rac1. This identifies Dock/ELMO as an effector complex of non-canonical Shh signaling and demonstrates the instructive role of GEFs in axon guidance.
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Project description:The therapeutic potential of neurotrophic factors has been hampered by their inability to achieve adequate tissue penetration. Brain blood vessels, however, could be an alternative target for neuro-salvage therapies by virtue of their close proximity to neurons. Here we show that hemizygous deletion of Rac1 in mouse endothelial cells (ECs) attenuates brain injury and edema following focal cerebral ischemia. To explore the mechanisms whereby decrease of Rac1 in ECs provide neuroprotection, ECs were derived from Rac1+/+ and Rac1+/- mice. Microarray analysis was performed to determine the differential gene expression between Rac1+/+ and Rac1+/- ECs. Rac1+/+ and Rac1+/- ECs were cultured to subconfluence. Total RNA was extracted and reverse transcribed. Rac1+/+ (n = 2) and Rac1+/- (n = 2) EC cDNAs were labeled with Cy3 and Cy5, respectively, and equimolar mixtures of labeled Rac1+/+ and Rac1+/- probes were hybridized to 2 slides (sample #21648, #21649). Additionally, Rac1+/+ (n = 2) and Rac1+/- (n=2) EC cDNAs labeled with Cy5 and Cy3 (dye-swapping) were hybridized to 2 slides (sample #21650, #21651). Comparison of signal intensities between Rac1+/+ (channel 2) and Rac1+/- (channel 1) was conducted on each slide (sample), and the ratio of intensities from 4 slides were statistically assessed for each gene feature to investigate differential gene expression.
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