Stitipragyan Bhumika

Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system

Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp‐2 and ‐13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp‐2 and ‐9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp‐14 expression decreased during regeneration. Altogether, a phase‐dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron‐intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472–1493, 2016.

Role of thyroid hormones in different aspects of nervous system regeneration in vertebrates

Spontaneous functional recovery from injury in the adult human nervous system is rare and trying to improve recovery remains a clinical challenge. Nervous system regeneration is a complicated sequence of events involving cell death or survival, cell proliferation, axon extension and remyelination, and finally reinnervation and functional recovery. Successful recovery depends on the cell-specific and time-dependent activation and repression of a wide variety of growth factors and guidance molecules. Thyroid hormones (THs), well known for their regulatory role in neurodevelopment, have recently emerged as important modulators of neuroregeneration. This review focuses on the endogenous changes in the proteins regulating TH availability and action in different cell types of the adult mammalian nervous system during regeneration as well as the impact of TH supplementation on the consecutive steps in this process. It also addresses possible differences in TH involvement between different vertebrate classes, early or late developmental stages and peripheral or central nervous system. The available data show that THs are able to stimulate many signaling pathways necessary for successful neurogeneration. They however also suggest that supplementation with T4 and/or T3 may have beneficial or detrimental influences depending on the dose and more importantly on the specific phase of the regeneration process.