Abstract
The regulation of neuronal soma size is essential for appropriate brain circuit function and its dysregulation is associated with several neurodevelopmental disorders. A defect in the dendritic growth and elaboration of motor neocortical pyramidal neurons in neonates lacking neuregulin-4 (NRG4) has previously been reported. In this study, we investigated if the loss of NRG4 causes further morphological defects that are specific to these neurons. We analysed the soma size of pyramidal neurons of layers 2/3 and 5 of the motor cortex and a subpopulation of multipolar interneurons in this neocortical region in Nrg4+/+ and Nrg4-/- mice. There were significant decreases in pyramidal neuron soma size in Nrg4-/- mice compared with Nrg4+/+ littermates at all stages studied (P10, P30 and P60). The reduction was especially marked at P10 and in layer 5 pyramidal neurons. Soma size was not significantly different for multipolar interneurons at any age. This in vivo phenotype was replicated in pyramidal neurons cultured from Nrg4-/- mice and was rescued by neuregulin-4 treatment. Analysis of a public single-cell RNA sequencing repository revealed discrete Nrg4 and Erbb4 expression in subpopulations of layer 5 pyramidal neurons, suggesting that the observed defects were due in part to loss of autocrine Nrg4/ErbB4 signalling. The pyramidal phenotype in the motor cortex of Nrg4-/- mice was associated with a lack of Rotarod test improvement in P60 mice, suggesting that absence of NRG4 causes alterations in motor performance.
Significance Statement Neuregulins are growth factors that are abundantly expressed in the nervous system where they regulate a plethora of processes essential for normal nervous system development and function in adulthood. Dysregulation of neuregulin signalling has been implicated in neurodevelopmental disorders, thus characterising the particular functions of members of this family of proteins is highly relevant for understanding how such disorders emerge. This study shows that neuregulin-4 is required to maintain motor cortex pyramidal neuron soma size, and that altered pyramidal neuronal morphology is associated with motor defects in mice.
Footnotes
Authors report no conflict of interest.
This work was supported by the Wellcome Trust Grant Number 103852 to AMD. BP was supported by a fellowship from CONACyT number 740520.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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