Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons

Abstract

SummaryNeural circuits in the cerebral cortex consist of excitatory pyramidal cells and inhibitory interneurons. These two main classes of cortical neurons follow largely different genetic programs, yet they assemble into highly specialized circuits during development following a very precise choreography. Previous studies have shown that signals produced by pyramidal cells influence the migration of cortical interneurons, but the molecular nature of these factors has remained elusive. Here, we identified Neuregulin 3 (Nrg3) as a chemoattractive factor expressed by developing pyramidal cells that guides the allocation of cortical interneurons in the developing cortical plate. Gain- and loss-of-function approaches reveal that Nrg3 modulates the migration of interneurons into the cortical plate in a process that is dependent on the tyrosine kinase receptor ErbB4. Perturbation of Nrg3 signaling in conditional mutants leads to abnormal lamination of cortical interneurons. Nrg3 is therefore a critical mediator in the assembly of cortical inhibitory circuits.

Developmental expression of Neuregulin‐3 in the rat central nervous system

“…To identify areas in which the Nrgs, including Nrg3, could have unique or shared functions, we compared the distribution of Nrg3 to that of Nrg1 Type III and Nrg2 mRNAs in P7 rat brains by in situ hybridization. Nrg3 showed high levels of hybridization throughout all cortical layers, as previously described (Bartolini et al, ; Longart et al, ) (Figures and and in Figure g,h). Nrg2 mRNA hybridization was detected throughout the Cx with the highest levels concentrated in the upper cortical layers (Figure d,e).…”

“…Nrg3 was highly expressed and widely distributed in the brain, compared to Nrg1 Type III and Nrg2. Our observations are consistent with and extend those of Longart et al (), Anton et al () and Bartolini et al (). Our findings have identified regions throughout the rodent CNS in which Nrg3 may play functional roles and highlight potential cellular model systems to study Nrg3 in health and disease.…”

“…Antibody staining will be required to ascertain the identity of these cells. In view of the aforementioned role of Nrg3 in cortical interneuronal cell migration (Bartolini et al, ), it will be of interest to determine whether it also plays a role in the migration of cerebellar granule neurons. Nrg1 has been previously shown to promote granule cell migration via an interaction with ErbB4, which is expressed on Bergmann glial fibers (Rio et al, ).…”

“…At E16, Zhang et al () observed that Nrg3 was predominantly expressed in neural tissue with high levels detected in the cortical plate (CxP). A recent effort has provided a detailed characterization of Nrg3 expression throughout early cortical development (E13.5–P4) (Bartolini et al, ). These investigators have determined that Nrg3 serves to regulate the migration of interneuronal precursors into distinct cortical layers.…”

“…Nrg3 is of particular interest as it has emerged as a candidate risk gene for several neuropsychiatric disorders including bipolar disorder and schizophrenia (SZ) (Avramopoulos, 2018; P. L. Chen et al, 2009;Hayes et al, 2016;Loos et al, 2014;Paterson et al, 2017). Recent studies have also indicated that Nrg3 plays important roles in cortical development (Bartolini et al, 2017) and glutamatergic neurotransmission (Wang et al, 2018). Along with studies on Nrg2 as a regulator of dopaminergic and glutamatergic function (Lee et al, 2015;Vullhorst et al, 2015;Yan et al, 2017), the current evidence supports the concept that Nrgs 1, 2, and 3 perform distinct functions in the central nervous system (CNS).…”