Diversification of multipotential postmitotic mouse retinal ganglion cell precursors into discrete types

Abstract

The genesis of broad neuronal classes from multipotential neural progenitor cells has been extensively studied, but less is known about the diversification of a single neuronal class into multiple types. We used single-cell RNA-seq to study how newly-born (postmitotic) mouse retinal ganglion cell (RGC) precursors diversify into ~45 discrete types. Computational analysis provides evidence that RGC type identity is not specified at mitotic exit, but acquired by gradual, asynchronous fate restriction of postmitotic multipotential precursors. Some types are not identifiable until a week after they are generated. Immature RGCs may be specified to project ipsilaterally or contralaterally to the rest of the brain before their type identity has been determined. Optimal transport inference identifies groups of RGC precursors with largely non-overlapping fates, distinguished by selectively expressed transcription factors that could act as fate determinants. Our study provides a framework for investigating the molecular diversification of discrete types within a neuronal class.

Rejection of inappropriate synaptic partners mediated by transcellular FLRT2-UNC5 signaling

“…These data are consistent with bulk and single-cell transcriptomic datasets, in which we found that Unc5c was not expressed at appreciable levels by DS circuit neurons (Kay et al, 2012; Shekhar et al, 2022; Tran et al, 2019; Yan et al, 2020). Using single-cell data (Yan et al, 2020), we identified 24 Unc5c- expressing amacrine cell types, 23 of which were GABAergic (Supplementary Fig.…”

“…When only a single one of these cadherins is deleted, ooDSGC phenotypes are quite mild – notably milder than the phenotype of Flrt2 and Unc5c single mutants (Duan et al, 2018). It is therefore possible that a more thorough disruption of the FLRT-UNC5-LPHN system would produce more profound phenotypes, particularly since Flrt3 is also expressed by a subset of DSGCs (Goetz et al, 2022; Ruff et al, 2021; Shekhar et al, 2022). Further work will be needed to test this possibility and thereby to assess the relative importance of the early vs. late laminar targeting systems.…”

“…Data from a separate P5 RGC dataset (Rheaume et al, 2018) was accessed via a web-based interface. Cell types within that dataset were identified based on cluster correspondences determined by Shekhar et al (2022).…”

A single-cell atlas of bobtail squid visual and nervous system highlights molecular principles of convergent evolution

“…described in vertebrate retinas. As with vertebrates, we anticipate that more extensive studies will subdivide these 26 cell types into subtypes based on function, connectivity and expression of marker genes (Cheng et al, 2021; Shekhar et al, 2016, 2021; Tran et al, 2019). In vertebrates, the ability to drive reporter gene expression and enrich for specific cell classes by cell sorting has been essential for detailed analysis; these tools are not yet available in cephalopods.…”

Cellular Mechanisms Underlying Embryonic Retinal Waves

“…Embryonic retinal development is a dynamic process involving cell death, proliferation, specification, migration, and process outgrowth. Specifically, concurrent with Stage 1 waves are RGC death and RGC subtype specific reduction in proliferation (Marcucci et al, 2019; Shekhar et al, 2022). The latter has been well characterized in intrinsically photosensitive retinal ganglion cells (ipRGCs) (McNeill et al, 2011) and the former has been observed across the general RGC population (Bähr, 2000; Braunger et al, 2014).…”