The m6A reader YTHDF2 is a negative regulator for dendrite development and maintenance of retinal ganglion cells.

Fugui Niu,Kezhen Tang,Bo Peng,Chunqiao Liu,Baisheng Yang,Yuwei Shi,Mengru Zhuang,Lixin Yang,Peng Han,Jun Yu,Yuanchu She,Jian Zhang,Sheng-Jian Ji

doi:10.7554/elife.75827

Abstract

The precise control of growth and maintenance of the retinal ganglion cell (RGC) dendrite arborization is critical for normal visual functions in mammals. However, the underlying mechanisms remain elusive. Here, we find that the N6-methyladenosine (m6A) reader YTHDF2 is highly expressed in the mouse RGCs. Conditional knockout (cKO) of Ythdf2 in the retina leads to increased RGC dendrite branching, resulting in more synapses in the inner plexiform layer. Interestingly, the Ythdf2 cKO mice show improved visual acuity compared with control mice. We further demonstrate that Ythdf2 cKO in the retina protects RGCs from dendrite degeneration caused by the experimental acute glaucoma model. We identify the m6A-modified YTHDF2 target transcripts which mediate these effects. This study reveals mechanisms by which YTHDF2 restricts RGC dendrite development and maintenance. YTHDF2 and its target mRNAs might be valuable in developing new treatment approaches for glaucomatous eyes.

Highlights

The mammalian retina is an ideal model system to study neuronal development and neural circuit formation
Distribution, the m6A reader YTHDF2 is highly expressed in retinal ganglion cell (RGC) (Figure 1A; Figure 1—figure supplement 1B)
The dendrite branching of RGCs with YTHDF1 KD using shYthdf1 was not significantly different from control shRNA (Figure 1—figure supplement 1K), while YTHDF3 KD using shYthdf3 caused a slight decrease of RGC dendrite branching compared with control shRNA (Figure 1—figure supplement 1L). These results suggest that the m6A reader YTHDF2 might play an important role in controlling dendrite branching of RGCs. 108 Conditional knockout of Ythdf2 in the retina increases RGC dendrite branching in vivo without disturbing sublaminar targeting To further explore whether YTHDF2 physiologically regulates RGC dendrite branching in vivo, we generated Ythdf2 conditional knockout (Ythdf2 cKO) mouse (Figure 2A)

Summary

Introduction

The mammalian retina is an ideal model system to study neuronal development and neural circuit formation. Existing evidences supported that homotypic repulsion controls retinal dendrite patterning (Lefebvre et al 2015). The fact that the dendrites of remaining RGC did not expand to neighboring areas by the remaining RGCs supports the existence of the intrinsic limit for RGC dendrite patterning, which cooperates with the homotypic repulsion to determine the dendrite size of RGCs (Lefebvre et al 2015).

Methods

Results

Conclusion