The angiopoietin-Tie2 pathway regulates Purkinje cell dendritic morphogenesis in a cell-autonomous manner

Luck, Robert; Karakatsani, Andromachi; Shah, Bhavin; Schermann, Géza; Adler, Heike; Kupke, Janina; Tisch, Nathalie; Jeong, Hyun‐Woo; Back, Michaela Kerstin; Hetsch, Florian; D’Errico, Anna; Palma, Michele De; Wiedtke, Ellen; Grimm, Dirk; Acker‐Palmer, Amparo; Engelhardt, Jakob von; Adams, Ralf H.; Augustin, Hellmut G.; Almodóvar, Carmen Ruiz de

doi:10.1016/j.celrep.2021.109522

Cited by 8 publications

(2 citation statements)

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“… 17 This type of paracrine signaling is common in the Angpt/Tie2 pathway and occurs, for example, between Purkinje, endothelial, and neural cells. 43 scRNAseq data from adult mice revealed that some TM cells had overlapping expression of both Angpt1 and Angpt4, whereas most TM cells expressed only either one (e.g., among the Angpt1 + JCT cells, 10.5% simultaneously expressed Angpt4, being 50% of Angpt4 + JCT cells). The lack of any SC defect in the Angpt1 fl/fl ; Angpt4 Cre/Cre mice, in which Angpt4 promoter–driven Cre expression (starting at P10) would prevent Angpt1 expression from the floxed allele if occurring in the same cells, also supports this observation.…”

Section: Discussionmentioning

confidence: 99%

Cooperation of Angiopoietin-2 and Angiopoietin-4 in Schlemm's Canal Maintenance

Kapiainen

Elamaa

Miinalainen

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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Purpose Defects in the iridocorneal angle tissues, including the trabecular meshwork (TM) and Schlemm's canal (SC), impair aqueous humor flow and increase the intraocular pressure (IOP), eventually resulting in glaucoma. Activation of endothelial tyrosine kinase receptor Tie2 by angiopoietin-1 (Angpt1) has been demonstrated to be essential for SC formation, but roles of the other two Tie2 ligands, Angpt2 and Angpt4, have been controversial or not yet characterized, respectively. Methods Angpt4 expression was investigated using genetic cell fate mapping and reporter mice. Congenital deletion of Angpt2 and Angpt4 and tamoxifen-inducible deletion of Angpt1 in mice were used to study the effects of Angpt4 deletion alone and in combination with the other angiopoietins. SC morphology was examined with immunofluorescent staining. IOP measurements, electron microscopy, and histologic evaluation were used to study glaucomatous changes. Results Angpt4 was postnatally expressed in the TM. While Angpt4 deletion alone did not affect SC and Angpt4 deletion did not aggravate Angpt1 deletion phenotype, absence of Angpt4 combined with Angpt2 deletion had detrimental effects on SC morphology in adult mice. Consequently, Angpt2 −/− ; Angpt4 −/− mice displayed glaucomatous changes in the eye. Mice with Angpt2 deletion alone showed only moderate SC defects, but Angpt2 was necessary for proper limbal vasculature development. Mechanistically, analysis of Tie2 phosphorylation suggested that Angpt2 and Angpt4 cooperate as agonistic Tie2 ligands in maintaining SC integrity. Conclusions Our results indicated an additive effect of Angpt4 in SC maintenance and Tie2 activation and a spatiotemporally regulated interplay between the angiopoietins in the mouse iridocorneal angle.

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Section: Discussionmentioning

confidence: 99%

Cooperation of Angiopoietin-2 and Angiopoietin-4 in Schlemm's Canal Maintenance

Kapiainen

Elamaa

Miinalainen

et al. 2022

Invest. Ophthalmol. Vis. Sci.

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“…4b ). Dnmt3a deficiency also led to downregulation of axon growth-inhibitory signals, such as Semaphorin 4 (SEMA4) 38 , and upregulation of synapse and axon growth-promoting signals, angiopoietin (ANGPT) 39,40 and secreted phosphoprotein 1/osteopontin (SPP1) 41 ( Fig. 4a ).…”

Section: Main Textmentioning

confidence: 99%

Suppressing DNMT3a Alleviates the Intrinsic Epigenetic Barrier for Optic Nerve Regeneration and Restores Vision in Adult Mice

Tai,

Cho,

Kriukov

et al. 2023

Preprint

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The limited regenerative potential of the optic nerve in adult mammals presents a major challenge for restoring vision after optic nerve trauma or disease. The mechanisms of this regenerative failure are not fully understood1,2. Here, through small-molecule and genetic screening for epigenetic modulators3, we identify DNA methyltransferase 3a (DNMT3a) as a potent inhibitor of axon regeneration in mouse and human retinal explants. Selective suppression of DNMT3a in retinal ganglion cells (RGCs) by gene targeting or delivery of shRNA leads to robust, full-length regeneration of RGC axons through the optic nerve and restoration of vision in adult mice after nerve crush injury. Genome-wide bisulfite and transcriptome profiling in combination with single nucleus RNA-sequencing of RGCs revealed selective DNA demethylation and reactivation of genetic programs supporting neuronal survival and axonal growth/regeneration by DNMT3a deficiency. This was accompanied by the suppression of gene networks associated with apoptosis and inflammation. Our results identify DNMT3a as the central orchestrator of an RGC-intrinsic mechanism that limits optic nerve regeneration. Suppressing DNMT3a expression in RGCs unlocks the epigenetic switch for optic nerve regeneration and presents a promising therapeutic avenue for effectively reversing vision loss resulted from optic nerve trauma or diseases.

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