Alternative Splicing for Activation of Coagulation Factor XIII-A in the Fish Retina After Optic Nerve Injury

Abstract

Factor XIII-A (FXIII-A), which has become known as cellular transglutaminase, plays important roles in mediating cross-linking reactions in various tissues. FXIII-A acts as one of the regeneration molecules in the fish retina and optic nerve after optic nerve injury and becomes activated at the site of injury within a few hours. Previous research has shown that activated FXIII-A induces neurite outgrowth from injured retinal ganglion cells and supports elongation of the regenerating optic nerve. However, the activation mechanism of FXIII-A remains unknown. Furthermore, the injured tissues do not express thrombin, a known activator of plasma FXIII. Here, we investigated the mRNA expression of FXIII-A based on two different regions, one encoding the activation peptide and the other encoding the enzymatic active site. We found that expression of the region encoding the activation peptide was markedly suppressed compared with the region encoding the active site. An overexpression study with a short-type FXIII-A cDNA lacking the activation peptide revealed induction of long neurite outgrowth in fish retinal explant cultures compared with full-length FXIII-A cDNA. The present findings suggest that alternative splicing may occur in the FXIII-A gene, resulting in deletion of the region encoding the activation peptide and thus allowing direct production of activated FXIII-A protein in the fish retina and optic nerve after optic nerve injury.

Specific Activation of Yamanaka Factors via HSF1 Signaling in the Early Stage of Zebrafish Optic Nerve Regeneration

“…When HSF1 -MO was pre-injected and the optic nerve was injured under conditions of suppressed HSF1 expression, numerous apoptotic cells were observed in all nuclear layers and the retinal layered structure was severely disrupted ( Figure S4 ). The long-lasting HSF1 gene expression must induce the gene expression of cell survival factors such as IGF-1, Bcl-2, and p-Akt 1–5 days after ONI [ 10 , 12 , 14 ]. Furthermore, the gene expression of OSK was induced rapidly and at the same time after ONI ( Figure 2 ).…”

“…Since the work of Sperry in the 1950s, the fish visual system has been the most popular model of CNS regeneration [ 4 , 5 , 6 , 7 , 8 , 9 ]. For the past 20 years, we have examined the regeneration of fish optic nerves from nerve crush to the recovery of visual function by using modern neurobiological tools such as immunohistochemistry [ 10 , 11 , 12 ], cell and tissue culture systems [ 13 , 14 , 15 ], and three-dimensional image processing systems for behavioral analysis [ 11 , 16 , 17 ]. The obtained results revealed that fish optic nerve regeneration includes (i) an early preparation period at 0–4 days; (ii) a middle neurite outgrowth period at 5–30 days; and (iii) a late synaptic refinement period at 1–4 months after optic nerve injury (ONI).…”

“…Some cell survival-related and anti-apoptotic factors were found to be induced in RGCs within 1–4 days after ONI such as insulin-like growth factor-I (IGF-I), Bcl-2, phospho-Akt (p-Akt), and phospho-Bad (p-Bad) [ 17 , 18 ]. Similarly, molecules such as purpurin [ 19 ], neuroglobin [ 20 , 21 ], and cellular factor XIII A subunit (cFXIII-A) [ 12 , 15 ] were induced in RGCs to activate neurite outgrowth. Heat shock factor 1 (HSF1) was most rapidly induced in RGCs at 0.5 h after ONI [ 22 , 23 , 24 ].…”