An Antagonistic Axon-Dendrite Interplay Enables Efficient Neuronal Repair in the Adult Zebrafish Central Nervous System

Abstract

Neural insults and neurodegenerative diseases typically result in permanent functional deficits, making the identification of novel pro-regenerative molecules and mechanisms a primary research topic. Nowadays, neuroregenerative research largely focuses on improving axonal regrowth, leaving the regenerative properties of dendrites largely unstudied. Moreover, whereas developmental studies indicate a strict temporal separation of axogenesis and dendritogenesis and thus suggest a potential interdependency of axonal and dendritic outgrowth, a possible axon-dendrite interaction during regeneration remains unexplored. To unravel the inherent dendritic response of vertebrate neurons undergoing successful axonal regeneration, regeneration-competent adult zebrafish of either sex, subjected to optic nerve crush (ONC), were used. A longitudinal study in which retinal ganglion cell (RGC) dendritic remodeling and axonal regrowth were assessed side-by-side after ONC, revealed that-as during development-RGC axogenesis precedes dendritogenesis during central nervous system (CNS) repair. Moreover, dendrites majorly shrank before the start of axonal regrowth and were only triggered to regrow upon RGC target contact initiation, altogether suggestive for a counteractive interplay between axons and dendrites after neuronal injury. Strikingly, both retinal mechanistic target of rapamycin (mTOR) and broad-spectrum matrix metalloproteinase (MMP) inhibition after ONC consecutively inhibited RGC synapto-dendritic deterioration and axonal regrowth, thus invigorating an antagonistic interplay wherein mature dendrites restrain axonal regrowth. Altogether, this work launches dendritic shrinkage as a prerequisite for efficient axonal regrowth of adult vertebrate neurons, and indicates that molecular/mechanistic analysis of dendritic responses after damage might represent a powerful target-discovery platform for neural repair.

Metformin Promotes Axon Regeneration after Spinal Cord Injury through Inhibiting Oxidative Stress and Stabilizing Microtubule

“…Therefore, it is meaningful to explore the approaches to promote axonal regeneration after. Recently, various neuroregenerative researches have focused on dendritic and axonal repair to improve functional recovery after CNS injury [51]. Previous studies have shown that metformin exerts neuroprotective effect and promotes functional recovery of memory deficits via anti-inflammation and triggering neurogenesis [52].…”

The receptor tyrosine kinase Ror is required for dendrite regeneration in Drosophila neurons

“…Dendrites can experience damage during traumatic brain injury (TBI) [8][9][10], and dendrite degeneration has been observed in neurodegenerative disease [11][12][13]. It has also been shown that dendrites simplify after axon damage [14][15][16][17]. In the case of retraction after axon injury, dendrites can re-elaborate if the axon reaches a target [15].…”

“…It has also been shown that dendrites simplify after axon damage [14][15][16][17]. In the case of retraction after axon injury, dendrites can re-elaborate if the axon reaches a target [15]. In vertebrate models, it has not been determined whether neurons can recover arbors after direct dendrite damage.…”

Cellular reprogramming for successful CNS axon regeneration is driven by a temporally changing cast of transcription factors

“…We hypothesized that regeneration-associated gene expression changes in axotomized RGCs would follow a temporal pattern corresponding to the changing requirements of axons as they grow through different environments leading from retina to optic tectum. The timing of successful axon regeneration after optic nerve crush in zebrafish is well characterized (7,8,20). To achieve a comprehensive picture of the genetic programming driving successful vertebrate CNS axon regeneration, we used RNA-seq to identify changes in gene expression that accompanied axon growth in regenerating RGCs at critical time points after optic nerve injury.…”

“…We specifically examined how transcript expression in naïve retinas compared with that in retinas dissected from fish at 2, 4, 7, and 12 days post-injury (dpi). Based on the previously established regeneration chronologies, our chosen time-points correspond to following stages of optic nerve regeneration: (a) axon growth past the site of injury toward the midline, (b) axon guidance across the midline, (c) selection of axon targets within the brain, and (d) synaptogenesis in the optic tectum ( (7,8,20); Fig. 1A).…”