Overexpression of neural miRNAs miR-9/9* and miR-124 suppresses differentiation to Müller glia and promotes differentiation to neurons in mouse retina in vivo.
Suzuki Fumiko,Okuno Mariko,Tanaka Tomoya,Sanuki Rikako
Genes to cells : devoted to molecular & cellular mechanisms
MicroRNAs (miRNAs) are known to regulate gene expression and modulate cellular differentiation. MicroRNA-9/9* (miR-9/9*) and microRNA-124 (miR-124) are highly expressed in the central nervous system. In vivo function of miR-9/9* and miR-124 have been investigated in detail, while there remain some discrepancies regarding neural development. To this end, we electroporated miR-9/9*, miR-124, or miR-9/9*/124 expression plasmids into neonatal retinal progenitor cells (RPCs) in vivo, and analyzed the fate of electroporated cells. Both miR-9/9* and miR-124 reduced the number of SOX9- and GS-positive cells and increased that of TUBB3-positive cells in the postnatal day 14 retina. No major effects on the proliferation and apoptosis of the electroporated cells were detected at least postnatal day 3. These indicated that miR-9/9* and miR-124 influence the cell-fate of glial cells, thereby inducing their differentiation into neurons. Moreover, we found this cell fate modulation was occurred in RPCs indicating high-level expression of miRNA, but not in the low-level. Our results strongly suggest that high-level miRNA overexpression is essential for directing cell-fate by miR-9/9* and miR-124 interference.
AIBP protects retinal ganglion cells against neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration.
Choi Soo-Ho,Kim Keun-Young,Perkins Guy A,Phan Sébastien,Edwards Genea,Xia Yining,Kim Jungsu,Skowronska-Krawczyk Dorota,Weinreb Robert N,Ellisman Mark H,Miller Yury I,Ju Won-Kyu
Glaucoma is a leading cause of blindness worldwide in individuals 60 years of age and older. Despite its high prevalence, the factors contributing to glaucoma progression are currently not well characterized. Glia-driven neuroinflammation and mitochondrial dysfunction play critical roles in glaucomatous neurodegeneration. Here, we demonstrated that elevated intraocular pressure (IOP) significantly decreased apolipoprotein A-I binding protein (AIBP; gene name Apoa1bp) in retinal ganglion cells (RGCs), but resulted in upregulation of TLR4 and IL-1β expression in Müller glia endfeet. Apoa1bp mice had impaired visual function and Müller glia characterized by upregulated TLR4 activity, impaired mitochondrial network and function, increased oxidative stress and induced inflammatory responses. We also found that AIBP deficiency compromised mitochondrial network and function in RGCs and exacerbated RGC vulnerability to elevated IOP. Administration of recombinant AIBP prevented RGC death and inhibited inflammatory responses and cytokine production in Müller glia in vivo. These findings indicate that AIBP protects RGCs against glia-driven neuroinflammation and mitochondrial dysfunction in glaucomatous neurodegeneration and suggest that recombinant AIBP may be a potential therapeutic agent for glaucoma.
Paired Immunoglobulin-like Receptor B Inhibition in Müller Cells Promotes Neurite Regeneration After Retinal Ganglion Cell Injury in vitro.
Yuan Rongdi,Yang Mei,Fan Wei,Lan Jian,Zhou Yuan-Guo
In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) have major inhibitory effects on nerve regeneration. They include Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein. MAIs possess two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Previous studies have confirmed that the inhibition of NgR only results in a modest increase in regeneration in the CNS; however, the inhibitory effects of PirB with regard to nerve regeneration after binding to MAIs remain controversial. In this study, we demonstrated that PirB is expressed in primary cultures of retinal ganglion cells (RGCs), and the inhibitory effects of the three MAIs on the growth of RGC neurites are not significantly decreased after direct PirB knockdown using adenovirus PirB shRNA. Interestingly, we found that retinal Müller cells expressed PirB and that its knockdown enhanced the regeneration of co-cultured RGC neurites. PirB knockdown also activated the JAK/Stat3 signaling pathway in Müller cells and upregulated ciliary neurotrophic factor levels. These findings indicate that PirB plays a novel role in retinal Müller cells and that its action in these cells may indirectly affect the growth of RGC neurites. The results also reveal that PirB in Müller cells affects RGC neurite regeneration. Our findings provide a novel basis for the use of PirB as a target molecule to promote nerve regeneration.