VEGF activates divergent intracellular signaling components to regulate retinal progenitor cell proliferation and neuronal differentiation

Abstract

During vertebrate neurogenesis, multiple extracellular signals influence progenitor cell fate choices. The process by which uncommitted progenitor cells interpret and integrate signals is not well understood. We demonstrate here that in the avascular chicken retina, vascular endothelial growth factor (VEGF) secreted by postmitotic neurons acts through the FLK1 receptor present on progenitor cells to influence cell proliferation and commitment. Augmenting VEGF signals increases progenitor cell proliferation and decreases retinal ganglion cell genesis. Conversely, absorbing endogenous VEGF ligand or disrupting FLK1 activity attenuates cell proliferation and enhances retinal ganglion cell production. In addition, we provide evidence that VEGF signals transmitted by the FLK1 receptor activate divergent intracellular signaling components, which regulate different responses of progenitor cells. VEGF-induced proliferation is influenced by the MEK-ERK pathway, as well as by the basic helix-loop-helix factor HES1. By contrast, VEGF-dependent ganglion cell suppression does not require MEK-ERK activation, but instead relies on VEGF-stimulated HES1 activity, which is independent of NOTCH signaling. Moreover, elevated HES1 expression promotes progenitor cell proliferation and prevents overproduction of retinal ganglion cells owing to the loss of VEGF or sonic hedgehog (SHH), another signal that suppresses ganglion cell development. Based on previous and current findings, we propose that HES1 serves as a convergent signaling node within early retinal progenitor cells to integrate various cell-extrinsic cues, including VEGF and SHH, in order to control cell proliferation and neuronal specification.

IGF‐1 receptor‐mediated ERK/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus

“…For example, neuromodulators such as cannabinoids, opioid, NPYas well as the mood stabilizer valproate increase neurogenesis via a MAPK-dependent mechanism (Hao et al, 2004;Howell et al, 2005;Jiang et al, 2005;Persson et al, 2003;Reuda et al, 2002). Furthermore, vascular endothelial growth factor-mediated proliferation of retinal progenitor cells is also dependent on MAPK signaling (Hashimoto et al, 2006), and using a slice culture technique, MAPK signaling has been shown to stimulate hypoxiainduced neurogenesis (Zhou and Miller, 2006;Zhou et al, 2004).…”

Vascular endothelial growth factor in eye disease

“…In adults, expression is generally restricted to the inner nuclear layer (Müller cells and amacrine cells), the ganglion cell layer, and the retinal vasculature (Stitt et al, 1998). However, during retinal neurogenesis VEGFR-2 is also expressed by neural progenitor cells (Hashimoto et al, 2006). Notably, neural cell VEGFR-2 can be activated by VEGF in vitro (Yang et al, 1996).…”

Molecular Control of Retinal Ganglion Cell Specification and Differentiation

“…Similarly, conditional ablation of Shh and Smoothened (Smo) in mice results in Atoh7-dependent overproduction of RGCs (Sakagami et al, 2009). VEGF (vascular endothelial growth factor) is also secreted by RGCs and other postmitotic neurons and can negatively regulate RGC differentiation (Hashimoto et al, 2006). Thus, RGC formation is reduced by enhanced VEGF signals but increased by disrupting VEGF signaling activity (Hashimoto et al, 2006).…”