Neuregulin-4 Is Required for Maintaining Soma Size of Pyramidal Neurons in the Motor Cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Neuronal soma size regulation is critical for brain function and its disruption is linked to neurodevelopmental disorders.
• Previous studies indicated neuregulin-4 (NRG4) deficiency affects dendritic growth in motor neocortical pyramidal neurons.

Purpose of the Study:

• To investigate if NRG4 deficiency causes further specific morphological defects in motor neocortical neurons.
• To determine the role of NRG4 in regulating pyramidal neuron soma size and associated motor functions.

Main Methods:

• Comparative analysis of pyramidal neuron soma size in wild-type (Nrg4+/+) and knockout (Nrg4-/-) mice at various postnatal stages (P10, P30, P60).
• In vitro culture of pyramidal neurons from Nrg4-/- mice with and without NRG treatment.
• Analysis of single-cell RNA sequencing data for Nrg4 and Erbb4 expression.
• Assessment of motor performance using the Rotarod test in Nrg4-/- mice.

Main Results:

• Significant reduction in pyramidal neuron soma size was observed in Nrg4-/- mice compared to controls, particularly in Layer 5 neurons at early stages.
• Multipolar interneuron soma size remained unaffected.
• The in vivo phenotype was replicated in cultured neurons and rescued by NRG treatment.
• Nrg4 and Erbb4 expression was detected in L5 pyramidal neurons, suggesting autocrine signaling.
• Nrg4 deficiency led to impaired motor performance in adult mice.

Conclusions:

• NRG4 is essential for maintaining normal pyramidal neuron soma size in the motor cortex.
• Loss of NRG4 impairs motor function, potentially due to disrupted autocrine Nrg4/ErbB4 signaling in pyramidal neurons.
• These findings identify NRG4 as a key regulator of neuronal morphology and motor behavior.