Regulation of fibronectin alternative splicing during peripheral nerve repair

Abstract

Wallerian degeneration following peripheral nerve injury is associated with increased production of fibronectin and other extracellular matrix molecules that are thought to enhance repair. We have shown previously that alternative splicing of the mRNA for fibronectin also changes following sciatic nerve lesions so as to reexpress forms of mRNA seen during embryogenesis. In the present study, we have examined the role of the regenerating axons in the regulation of this splicing. We have compared the patterns of fibronectin mRNA splicing seen in sciatic nerve development with that seen in cut nerves (that do not regenerate), crushed nerves (that regenerate successfully), and Schwann cells cultured in forskolin so as to mimic axonal signals. By using a reverse transcriptase polymerase chain reaction assay to examine all three regions of fibronectin mRNA splicing in a quantitative manner, we found that embryonic patterns of fibronectin mRNA splicing appear rapidly following injury and are not then altered by reestablishment of axons in the nerve. In addition, we found that forskolin has no effect on fibronectin mRNA splicing in cultured cells. We conclude that axonal signals do not regulate the pattern of fibronectin alternative splicing in peripheral nerve repair.

Fibronectin is a binding partner for the myelin‐associated glycoprotein (siglec‐4a)

“…Examples are a di¡use strong protein band of apparently 300 kDa and proteins of 190, 110, 62 and 58 kDa. Furthermore, several proteins are more pronounced in preparations from adult animals or are only found in these preparations (36,90, 100, 120, 130, 150, 170 and 210 kDa). Changes were also observed if MAG binding partners from spinal cords of di¡erent aged rats were analyzed (Fig.…”

“…Interestingly, the repair of nerves in the peripheral nervous system is associated with the reappearance of embryonal forms of Fn mRNA [36]. This suggests that the re-expression of embryonic Fn may be important for successful repair in the peripheral nervous system and that a development-and tissue repair-dependent expression of di¡erent spliced Fn isoforms may be involved in regulation of growth processes or stability.…”

Activating Transcription Factor 3 and the Nervous System

“…In transformed mammary epithelial cells ATF3 enhanced fibronectin expression (Yin et al, 2010), which may exert a growth-promoting effect (Vogelezang et al, 1999). In untransformed chick fibroblasts ATF3 also repressed the expression of decorin (Perez et al, 2001; Yin et al, 2010), a TGFb-binding glycoprotein which may reduce scarring and thus promote regeneration (Davies et al, 2004).…”

Extrinsic cellular and molecular mediators of peripheral axonal regeneration

“…Interestingly, peripheral nerve injury leads to an increased expression of specific embryonic isoforms of fibronectin, containing the type III connecting segment (IIICS). By this means, not only increased amounts of fibronectin are present in the lesioned nerve, offering a favored substrate for Schwann cell migration but developmental splice variants with improved properties for neuronal adhesion and axonal growth are also re-expressed during nerve repair (Gardiner et al 2011;Vogelezang et al 1999;Mathews and ffrench-Constant 1995). Although fibronectin and collagen appear less effective than laminin in promoting axonal outgrowth of adult peripheral neurons, a preconditioning crush lesion markedly enhances neurite outgrowth on fibronectin (Gardiner et al 2007).…”