Project Details
Projekt
Interplay between serotonergic and L1-mediated signaling in regulation of neuronal morphology and functions under physiological and pathological conditions
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2015 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 299063188
Stress-related disorders are shown to be associated with functional disturbance of neuronal adhesion molecule L1. The L1-mediated neuronal migration, development, and regeneration based on homo/ heterophilic L1 interactions seems to be depended on presentation of L1 either as a membrane-bound form or as a proteolytic fragments. In our preliminary experiments we have identified the neuronal L1 as a proteolytic substrate for the matrix metalloproteinase-9 (MMP-9) and demonstrated that L1 fragments generated by MMP-9 cleavage are involved in spine formation in dissociated hippocampal neurons. Together with the observation that the L1 can initiate neurite outgrowth via phosphorylation of actin-binding protein cofilin, this data suggests that MMP-9-mediated proteolysis of L1 might be involved in L1-initiated signaling pathway regulating actin rearrangement in neurons.Serotonergic system has been identified as crucially important to the pathophysiology and the treatment of mood disorders. Neurotransmitter serotonin (5-HT) regulates a wide range of physiological and pathological functions, and is involved in neurite outgrowth, growth cone motility and synaptogenesis. Serotonin operates via activation of multiple 5-HT receptors, whereby in this project we will focus on the 5-HT4 receptor (5-HT4R). In the mammalian brain this receptor contributes to regulation of learning and long term memory and is involved in various central and peripheral disorders, including neurodegenerative disease and depression. In our preliminary results we have shown that stimulation of 5-HT4R induces the release of enzymatically active MMP-9 in hippocampal neurons, where 5-HT4R and L1 are tightly co-localized at the synapses. These results demonstrate that 5-HT4R might regulate L1 shedding in an MMP-9-dependent manner, thereby modulating the homo/heterophilic interaction and paracrine function of L1. We have previously shown that 5-HT4R stimulation results in activation of the small GTPase RhoA, leading to cell rounding and neurite retraction. In our preliminary experiments we have also demonstrated that this effect can be mediated by phosphorylation of cofilin. Thus, cofilin may represent a common downstream effector for both 5-HT4R and L1 suggesting that 5-HT4R, MMP-9 and L1 belong to the same signaling module involved in regulation of neuronal morphology.Within this proposal we will study molecular mechanisms of 5-HT4R-mediated L1 processing as well as the functional implication of L1 fragments for neural development and survival. For that we will combine biochemical, molecular and cellular approaches with advanced Förster resonance energy transfer (FRET) techniques and quantitative molecular microscopy. From these investigations we expect to reveal a novel molecular mechanisms by which serotonin can regulate formation and plasticity of neuronal networks, and hope to provide new targets for pharmacological treatment of stress-associated disorders, including depression.
DFG Programme
Research Grants
