Role for Reelin‐induced cofilin phosphorylation in the assembly of sympathetic preganglionic neurons in the murine intermediolateral column

Abstract

Sympathetic preganglionic neurons (SPNs) are located in the intermediolateral column (IMLC) of the spinal cord. This specific localization results from primary and secondary migratory processes during spinal cord development. Thus, following neurogenesis in the neuroepithelium, SPNs migrate first in a ventrolateral direction and then, in a secondary step, dorsolaterally to reach the IMLC. These migratory processes are controlled, at least in part, by the glycoprotein Reelin, which is known to be important for the development of laminated brain structures. In reeler mutants deficient in Reelin, SPNs initially migrate ventrolaterally as normal. However, most of them then migrate medially to become eventually located near the central canal. Here, we provide evidence that in wild-type animals this aberrant medial migration towards the central canal is prevented by Reelin-induced cytoskeletal stabilization, brought about by phosphorylation of cofilin. Cofilin plays an important role in actin depolymerization, a process required for the changes in cell shape during migration. Phosphorylation of cofilin renders it unable to depolymerize F-actin, thereby stabilizing the cytoskeleton. Using immunostaining for phosphorylated cofilin (p-cofilin), we demonstrate that SPNs in wild-type animals, but not in reeler mutants and other mutants of the Reelin signalling cascade, are immunoreactive for p-cofilin. These findings suggest that Reelin near the central canal induces cofilin phosphorylation in SPNs, thereby preventing them from aberrant migration towards the central canal. The results extend our previous studies on cortical neurons in which Reelin in the marginal zone was found to stabilize the leading processes of migrating neurons and terminate the migration process.

Dab1 Is Required for Synaptic Plasticity and Associative Learning

“…Indeed, Reelin signaling promotes the activation of NMDARs through tyrosine phosphorylation of the NR2A and NR2B cytoplasmic tails, leading to increased calcium influx (Chen et al, 2005). Combined, these mechanisms could explain the observed changes in spine morphology in the Dab1 cKO mice; however, potential direct effects of Reelin on the actin cytoskeleton, as seen during development (Krüger et al, 2010), cannot be presently excluded. Given that spine morphology represents a continuum of different shapes, in this study we did not conduct a classification of different spine subtypes.…”

“…However, at least one study did not report similar defects in heterozygous reeler mice (Krueger et al, 2006). An ApoER2 isoform capable of binding postsynaptic density (PSD)-95 has been further implicated in synaptic plasticity and cognition through a mechanism involving the NMDA receptor (NMDAR; .…”

Sorting Nexin 17 Regulates ApoER2 Recycling and Reelin Signaling

“…Together with VLDL-R, which is another member of the LDL-R family [4], and Ephrin [5], ApoER2 binds the extracellular matrix protein reelin during development [4], [6], triggering a signaling pathway that regulates neuronal migration and the formation of laminated brain structures such as the cortex, hippocampus [7] and cerebellum [4] as well as the migration of sympathetic preganglionic neurons in the spinal cord [8], [9]. Reelin binding to ApoER2 induces binding of the adaptor protein Dab1 to its cytoplasmic NPxY motif [10], [11], resulting in the phosphorylation of specific tyrosines [12], [13], PI3K activation, and n-cofilin phosphorylation in the leading processes of migrating neurons [9], [14]. In the adult, ApoER2/reelin have roles in synaptic function, learning, and memory.…”

Extracellular matrix protein reelin regulate dendritic spine density through CaMKIIβ

“…This is because dendritic spines have high concentrations of actin fibers at excitatory synapses, and actin affects the size and the synaptic strength of the dendritic spine [22][23]. Interestingly, recent studies have shown that Reelin alters the actin cytoskeleton dynamics through n-cofilin, which is important for dendiritc spine stability [24][25]. Another study has shown that Reelin regulates actin and microtubule cytoskeletal organization by modulating cdc42 [26].…”