Sprouty2 inhibits BDNF-induced signaling and modulates neuronal differentiation and survival

Abstract

Sprouty (Spry) proteins are ligand-inducible inhibitors of receptor tyrosine kinases-dependent signaling pathways, which control various biological processes, including proliferation, differentiation and survival. Here, we investigated the regulation and the role of Spry2 in cells of the central nervous system (CNS). In primary cultures of immature neurons, the neurotrophic factor BDNF (brain-derived neurotrophic factor) regulates spry2 expression. We identified the transcription factors CREB and SP1 as important regulators of the BDNF activation of the spry2 promoter. In immature neurons, we show that overexpression of wildtype Spry2 blocks neurite formation and neurofilament light chain expression, whereas inhibition of Spry2 by a dominantnegative mutant or small interfering RNA favors sprouting of multiple neurites. In mature neurons that exhibit an extensive neurite network, spry2 expression is sustained by BDNF and is downregulated during neuronal apoptosis. Interestingly, in these differentiated neurons, overexpression of Spry2 induces neuronal cell death, whereas its inhibition favors neuronal survival. Together, our results imply that Spry2 is involved in the development of the CNS by inhibiting both neuronal differentiation and survival through a negative-feedback loop that downregulates neurotrophic factors-driven signaling pathways.

Sprouty2-Mediated Inhibition of Fibroblast Growth Factor Signaling Is Modulated by the Protein Kinase DYRK1A

“…This has been observed by immunofluorescence analysis in brain sections as well as in dissociated cultures of cortical neurons. A similar staining pattern has been reported in primary cultures of cerebellar granule neurons (18), pointing to a not-yet-known nuclear role for Spry2.…”

Characterisation of a new regulator of BDNF signalling, Sprouty3, involved in axonal morphogenesis in vivo

“…Despite all the data reported on Spry function, the molecular mechanisms by which Spry family members regulate branching are still unclear. In mammalian tissue culture systems, Spry proteins have been shown to inhibit Erk activation downstream of a plethora of growth factors, including FGF, VEGF-A, BDNF and GDNF (Cabrita and Christofori, 2008;Gross et al, 2007;Impagnatiello et al, 2001;Ishida et al, 2007;Taniguchi et al, 2009a). In Xenopus embryos, we have shown that Spry1 and Spry2 inhibit the Ca 2+ pathway downstream of FGF (Nutt et al, 2001;Sivak et al, 2005).…”

“…Knockdown of Spry2 expression in murine embryonic lung cells in culture enhances branching morphogenesis (Tefft et al, 1999). In PC12 cells and cerebellar granule neurons (CGNs), overexpression of Spry2 reduces the number of neurites (Gross et al, 2007;Hanafusa et al, 2002;Sasaki et al, 2001). However, there is still a lack of evidence to support a role for Spry in axonal branching, as none of the knockouts reported to date shows a defect in the central nervous system.…”

Overexpression Screen in Drosophila Identifies Neuronal Roles of GSK-3β/shaggyas a Regulator of AP-1-Dependent Developmental Plasticity

“…Sprouty is a ligand-activated inhibitor that antagonizes receptor tyrosine kinase signaling in several contexts, such as Ras/ERK signaling in the developing compound eye (Kramer et al 1999;Hanafusa et al 2002). More notably, sprouty2-dependent signaling negatively regulates survival, differentiation, and growth in cultured immature neurons by antagonizing brain-derived neurotrophic factor (BDNF)-dependent signaling (Gross et al 2007). Precise analysis of this negative regulator in neural development and plasticity, however, has been lacking so far.…”