A potential role for somatostatin signaling in regulating retinal neurogenesis

Abstract

Neuropeptides have been reported to regulate progenitor proliferation and neurogenesis in the central nervous system. However, these studies have typically been conducted using pharmacological agents in ex vivo preparations, and in vivo evidence for their developmental function is generally lacking. Recent scRNA-Seq studies have identified multiple neuropeptides and their receptors as being selectively expressed in neurogenic progenitors of the embryonic mouse and human retina. This includes Sstr2, whose ligand somatostatin is transiently expressed by immature retinal ganglion cells. By analyzing retinal explants treated with selective ligands that target these receptors, we found that Sstr2-dependent somatostatin signaling induces a modest, dose-dependent inhibition of photoreceptor generation, while correspondingly increasing the relative fraction of primary progenitor cells. These effects were confirmed by scRNA-Seq analysis of retinal explants but abolished in Sstr2-deficient retinas. Although no changes in the relative fraction of primary progenitors or photoreceptor precursors were observed in Sstr2-deficient retinas in vivo, scRNA-Seq analysis demonstrated accelerated differentiation of neurogenic progenitors. We conclude that, while Sstr2 signaling may act to negatively regulate retinal neurogenesis in combination with other retinal ganglion cell-derived secreted factors such as Shh, it is dispensable for normal retinal development.

A single-cell guide to retinal development: Cell fate decisions of multipotent retinal progenitors in scRNA-seq

“…In non-retinal tissues, Sstr2 functions as a somatostatin (Sst) receptor, that upon activation, functions to control of cell-cycle exit through accumulation of the downstream effector and cell-cycle inhibitor, p21 (Cdkn1a; Alderton et al, 2001 ). scRNA-seq of both Sstr2 knockout retinas or Sstr2 agonist-treated retinal explants indicate that Sstr2-activation may function to inhibit neurogenesis and specification of photoreceptors within the developing retina ( Weir et al, 2021 ). In this instance, scRNA-seq studies failed to detect large-scale transcriptional changes after either activation or inhibition of Sstr2 signaling, suggesting an inherent level of functional redundancy in the control of retinal neurogenesis.…”

LRLoop: Feedback loops as a design principle of cell-cell communication

“…Similarly, 11 known ligand-receptor interactions were identified between RPC and neurogenic cells, including multiple Notch-Delta pathway members (Supplementary Figure 2D) [23]. Interactions identified between RGC and neurogenic progenitors included Sst-Sstr2, which is known to play a role in photoreceptor generation and regulation of retinal neurogenesis [24] (Figure 4C, D).…”

Somatostatin affects GnRH neuronal development and migration and stimulates olfactory‐related fiber fasciculation

“…In addition to the involvement of SST in the regulation of brain neurogenesis, a recent scRNA‐seq study demonstrated the potential role of SSTR2 signaling in retinal neurogenesis. The expression of SST and SSTR2 was found in immature retinal ganglion cells, and SSTR2‐activation modestly inhibited photoreceptor generation in retinal explants (Weir et al., 2021). Another recent study demonstrated that SST potentiates the regulation of the subcellular distribution and expression of neurotransmitters in the retinoic acid‐induced differentiation of human neuroblastoma cells (Singh et al., 2022).…”