Modular and Distinct Plexin-A4/FARP2/Rac1 Signaling Controls Dendrite Morphogenesis.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Neuronal morphology is critical for nervous system function.
• The Sema3A-Nrp1/PlxnA4 pathway influences both axon guidance and dendrite development.
• Downstream signaling of Sema3A's dual functions remains unclear.

Purpose of the Study:

• To elucidate the downstream signaling components of the Sema3A-Nrp1/PlxnA4 pathway.
• To determine the specific roles of the PlxnA4 cytoplasmic domain, particularly the KRK motif, in mediating Sema3A's functions.
• To identify novel signaling molecules involved in Sema3A-mediated neuronal development.

Main Methods:

• Generation of novel PlxnA4 knock-in mice using CRISPR/cas9.
• Analysis of PlxnA4 KRK motif function in Sema3A signaling.
• Investigation of FARP2 and Rac1 involvement in the pathway.
• Assessment of effects on cortical neuron dendritic elaboration and axon guidance.

Main Results:

• The KRK motif in PlxnA4 is required for Sema3A-induced dendritic elaboration but not for axon repulsion.
• FARP2, a RhoGEF binding to the KRK motif, exhibits similar functional specificity.
• Sema3A activates Rac1, which is necessary for dendrite elaboration but not axon growth cone collapse.

Conclusions:

• A novel Sema3A-Nrp1/PlxnA4/FARP2/Rac1 signaling pathway specifically controls dendritic morphogenesis.
• This pathway is distinct from the one mediating repulsive axon guidance.
• Multifunctional receptor complexes achieve divergent signaling outputs through distinct motifs, demonstrating modularity in guidance cue receptors.