Reelin activates the small GTPase TC10 and VAMP7 to promote neurite outgrowth and regeneration of dorsal root ganglia (DRG) neurons

Abstract

Axonal outgrowth is a fundamental process during the development of central (CNS) and peripheral (PNS) nervous system as well as in nerve regeneration and requires accurate axonal navigation and extension to the correct target. These events need proper coordination between membrane trafficking and cytoskeletal rearrangements and are under the control of the small GTPases of the Rho family, among other molecules. Reelin, a relevant protein for CNS development and synaptic function in the adult, is also present in the PNS. Upon sciatic nerve damage, Reelin expression increases and, on the other hand, mice deficient in Reelin exhibit an impaired nerve regeneration. However, the mechanism(s) involved the Reelin‐dependent axonal growth is still poorly understood. In this work, we present evidence showing that Reelin stimulates dorsal root ganglia (DRG) regeneration after axotomy. Moreover, dissociated DRG neurons express the Reelin receptor Apolipoprotein E‐receptor 2 and also require the presence of TC10 to develop their axons. TC10 is a Rho GTPase that promotes neurite outgrowth through the exocytic fusion of vesicles at the growth cone. Here, we demonstrate for the first time that Reelin controls TC10 activation in DRG neurons. Besides, we confirmed that the known CNS Reelin target Cdc42 is also activated in DRG and controls TC10 activity. Finally, in the process of membrane addition, we found that Reelin stimulates the fusion of membrane carriers containing the v‐SNARE protein VAMP7 in vesicles that contain TC10. Altogether, our work shows a new role of Reelin in PNS, opening the option of therapeutic interventions to improve the regeneration process.

Role of VAMP7-Dependent Secretion of Reticulon 3 in Neurite Growth

“…Our previous work and that of others suggested an important role of VAMP7-dependent secretion in neuronal development (Alberts et al, 2003;Burgo et al, 2012Burgo et al, , 2013Colombo et al, 2014;Fuschini et al, 2018;Gupton and Gertler, 2010;Jausoro and Marzolo, 2021;Martinez-Arca et al, 2000. These results were based on mRNA silencing approaches and expression of the auto-inhibitory Longin domain in cultured neurons and NGF-treated PC12 cells.…”

Transplantation of bioengineered Reelin‐loadedPLGA/PEGmicelles can accelerate neural tissue regeneration in photothrombotic stroke model of mouse

“…71 It was suggested that Reelin can stimulate the regeneration of dorsal root ganglia following axotomy. 72 Of note, the injection of purified Reelin increases the regional density of the dendritic spine and hippocampal CA1 long‐term potentiation coincides with spatial learning and memory, showing Reelin activity on synaptic function and cognitive performance in rodents. 73 Therefore, it can be proposed that the reduction of astrocytes in the injured sites correlates with the promotion of neurogenesis, leading to a reduction of astrocyte recruitment into the injured sites.…”

“…Based on the great body of experiments, three‐dimensional biomaterials not only offer a supportive environment for the transplanted cells, but also is capable of reducing glial scar formation 71 . It was suggested that Reelin can stimulate the regeneration of dorsal root ganglia following axotomy 72 . Of note, the injection of purified Reelin increases the regional density of the dendritic spine and hippocampal CA1 long‐term potentiation coincides with spatial learning and memory, showing Reelin activity on synaptic function and cognitive performance in rodents 73 .…”

TOM-1/tomosyn acts with the UNC-6/netrin receptor UNC-5 to inhibit growth cone protrusion in Caenorhabditis elegans

“…Vesicle exocytosis is required for growth cone membrane extensions by fusion of plasmalemmal precursor vesicles at the plasma membrane of growth cones and is closely tied to cytoskeletal dynamics ( Futerman and Banker, 1996 ; Hausott and Klimaschewski, 2016 ; Nozumi and Igarashi, 2018 ), and a balance of endocytosis and exocytosis is involved in growth cone guidance ( Tojima et al, 2014 ; Tojima and Kamiguchi, 2015 ). The axon guidance cue reelin controls fusion of VAMP7-positive vesicles in regenerating dorsal root ganglion neurons ( Jausoro and Marzolo, 2021 ). Furthermore, synaptic-like vesicles in the growth cone are required for pioneer axon navigation in zebrafish ( Nichols and Smith, 2019 ).…”