Tenascin C regulates proliferation and differentiation processes during embryonic retinogenesis and modulates the de-differentiation capacity of Müller glia by influencing growth factor responsiveness and the extracellular matrix compartment

Abstract

The retina represents an ideal model system for studying developmental processes during morphogenesis. The knowledge of the precise regulation and combination of genetic pre-dispositions and environmental circumstances enables the understanding of pathologies and the subsequent development or/and improvement of therapeutic strategies. This study focused on the functional analysis of the extracellular matrix (ECM) molecule Tenascin C (Tnc) in the retinal stem/progenitor cell environment. In this perspective, a Tnc(-/-) mouse was examined for potential alterations in proliferation and differentiation programs by using immunohistochemistry, RT-PCR analysis and bioassays. It could be shown that both cycling G2-phase cells and early post-mitotic neurons were significantly increased in the retina due to Tnc-deficiency. Further investigations suggested that Tnc regulates these processes via the Wnt-signaling cascade. Therapeutic approaches in the treatment of degenerative diseases often integrate cell-replacement strategies. Retinal Müller glia cells represent the glia of the retina and are described to possess the ability to re-enter the cell cycle and generate neurons in response to injury. In this study, the de-differentiation was induced by FGF2. It was found out that Tnc influences the de-differentiation behavior of adherent Müller glia in vitro. Moreover, it was interesting to investigate the effect of the absence of Tnc on the composition of other components of the ECM. A special focus lay on the expression of a specifically sulfated carbohydrate motif on chondroitin sulfate glycosaminoglycan chains, which can be detected with the mAb 473HD. It was possible to note a significant increase of this particular chondroitin sulfate in the Tnc-deficient ECM.

The extracellular matrix glycoprotein tenascin-R regulates neurogenesis during development and in the adult dentate gyrus of mice

“…Ablation of tenascin-C (TNC) in the neurogenic niche promotes the generation of neurons and influenced proliferation of oligodendrocyte precursors, radial glial cells, and retinal stem/ progenitor cell by regulating the cell-cycle exit (Besser et al, 2012;Czopka et al, 2009;Garcion et al, 2001;Garcion et al, 2004). Interestingly, TNC 2/2 mice show a reduction in expression of ASCL1 (Mash1) by retinal stem/progenitor cells (Besser et al, 2012), in contrast to our study where TNR deficiency resulted in increased ASCL1 expression in NSCs in the ganglionic eminence. Enzymatic degradation of chondroitin sulfate expressed by proteoglycans in the stem cell niche promotes differentiation and migration of neural progenitor cells (Gu et al, 2009), indicating an influence of these extracellular matrix molecules on neurogenesis.…”

Glia–neuron interactions in the mammalian retina

“…TN-C is important in this process as it enhances Müller cell sensitivity to FGF2. Moreover, dedifferentiation was found to be impaired in TN-C knock-out mice (Besser et al, 2012).…”

Involvement of the guanine nucleotide exchange factor Vav3 in central nervous system development and plasticity

“…Beyond these aspects, both small GTPases and Vav genes are expressed in the developing retina (Mitchell et al, 2007;Fujikawa et al, 2010). Also, we could show that the glycoprotein tenascin-C regulates the proliferation of early born neurons and supports the FGF2-induced proliferation and de-differentiation of Müller glia stem cells in the retina (Besser et al, 2012). In the light of these observations, we carefully monitored the development of the distinct lineages of the retina in our Vav3 -/-model.…”