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Signalling Pathways Mediating the Effects of CD40-Activated CD40L Reverse Signalling on Inhibitory Medium Spiny
Paulina Carriba1, Alun M Davies1
1School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
Cells
|April 30, 2021
Summary
CD40L reverse signaling differentially regulates neurite growth in the central nervous system. It promotes growth in excitatory neurons but restricts it in inhibitory neurons via distinct signaling networks.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- CD40L-mediated reverse signaling is crucial for neurite development in the central nervous system (CNS).
- This signaling pathway has opposing effects on excitatory pyramidal neurons (promoting growth) and inhibitory medium spiny neurons (MSNs, restricting growth).
- Previous studies identified interconnected signaling networks involving protein kinase C (PKC), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-Jun N-terminal kinase (JNK) in pyramidal neurons.
Purpose of the Study:
- To investigate whether the same signaling pathways (PKC, ERK1/2, JNK) influence neurite growth in inhibitory MSNs.
- To compare the signaling mechanisms underlying CD40L reverse signaling's opposing effects on excitatory and inhibitory neurons.
- To elucidate the specific roles and interdependencies of these pathways in MSN neurite development.
Main Methods:
- Treatment of CD40-deficient MSN cultures with CD40-Fc to activate CD40L reverse signaling.
- Pharmacological manipulation using activators and inhibitors of PKC, ERK1/2, and JNK signaling pathways.
- Immunoprecipitation studies to identify protein interactions, specifically the recruitment of Syk tyrosine kinase.
Main Results:
- CD40L reverse signaling activation in MSNs increased phosphorylation of PKC, ERK1/2, and JNK.
- These pathways form an interconnected network regulating MSN neurite growth, but with different functions and interdependencies compared to pyramidal neurons.
- Syk tyrosine kinase recruitment was observed upon CD40L reverse signaling stimulation, notably without PKC participation, unlike in pyramidal neurons.
Conclusions:
- Distinct signaling pathway networks mediate the opposing effects of CD40L reverse signaling on neurite growth in excitatory and inhibitory neurons.
- The interplay between PKC, ERK1/2, and JNK signaling is critical for neurite development in both neuron types, but with unique regulatory mechanisms.
- These findings highlight the nuanced and cell-type-specific roles of CD40L reverse signaling in CNS development.
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