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

Abstract

Neuregulin‐3 (Nrg3) is a member of the Nrg family of growth factors identified as risk factors for schizophrenia. There are three Nrgs expressed in the nervous system (Nrg1‐3) and of these Nrg1 has been the best characterized. To set the groundwork for elucidating neural roles for Nrg3, we studied its expression in the rat brain at both the RNA and protein levels. Using an antibody developed against Nrg3, we observed a developmental increase of Nrg3 protein expression from embryonic stages to adulthood and determined that it carries O‐linked carbohydrates. In cortical neuronal cultures, transfected Neuro2a cells, and brain tissue sections Nrg3 protein was localized to the soma, neurites, and to the Golgi apparatus, where it is prominently expressed. Nrg3 was detected in excitatory, GABAergic and parvalbumin‐expressing inhibitory neurons while expression in glia was limited. Nrg3 mRNA and protein were widely expressed during both embryonic and postnatal ages. At E17, Nrg3 was detected within the cortical plate and ventricular zone suggesting possible roles in cell proliferation or migration. At postnatal ages, Nrg3 was abundantly expressed throughout the cerebral cortex and hippocampus. Multiple thalamic nuclei expressed Nrg3, while detection in the striatum was limited. In the cerebellum, Nrg3 was found in both Purkinje cells and granule neurons. In the rodent brain, Nrg3 is the most abundantly expressed of the Nrgs and its patterns of expression differ both temporally and spatially from that of Nrg1 and Nrg2. These findings suggest that Nrg3 plays roles that are distinct from the other Nrg family members.

Neuregulin and ErbB expression is regulated by development and sensory experience in mouse visual cortex

“…NRG3 also signals through the ErbB4 receptor, but the nature of this adult NRG3/ErbB4 signaling is not well understood, and NRG3 has a much lower affinity for ErbB4 than NRG1 (Hobbs et al, ; Jones et al, ; Zhang et al, ), which could differentially influence signaling. NRG3 has been reported to be expressed by inhibitory and PV interneurons (Muller et al, ; Rahman et al, ). Neither nrg2 nor nrg4 expression by PV cells is strong, and do not change between P28 and P104 (Figure b).…”

“…NRG3 is expressed very strongly throughout the cortex during development and adulthood (Anton et al, ; Bartolini et al, ; Li, Chou, Hamasaki, Perez‐Garcia, & O'Leary, ; Longart, Liu, Karavanova, & Buonanno, ; Loos et al, ; Rahman, Weber, Labin, Lai, & Prieto, ; Zhang et al, ). Alternatively, NRG2 and NRG4 are present in adult cortex, but not at very high levels (Anton et al, ; Longart et al, ; Paramo, Wyatt, & Davies, ; Yan et al, ).…”

“…Both NRG2 and NRG4 are ligands for the ErbB4 receptor, but their relative affinities in vivo are unclear (Carraway et al, ; Harari et al, ). NRG3 is thought to be expressed presynaptically from excitatory neuron axons that synapse onto ErbB4 expressing dendrites of PV interneurons in order to stabilize the synapse (Bartolini et al, ; Muller et al, ; Rahman et al, ; Vullhorst, Ahmad, Karavanova, Keating, & Buonanno, ). Supporting this interaction are the findings that both NRG3 and ErbB4 mutant mice have increased gamma oscillations (Del Pino et al, ; Muller et al, ).…”

Subcellular sorting of neuregulins controls the assembly of excitatory-inhibitory cortical circuits

“…Neuregulins comprise a family of growth factors that activate receptor tyrosine kinases of the ErbB family ( Mei and Nave, 2014 ). Type III Neuregulin 1 (hereafter referred to as Nrg1) and Neuregulin 3 (Nrg3) are the most abundantly expressed neuregulins in the cerebral cortex during the period of synaptogenesis ( Fazzari et al, 2010 ; Longart et al, 2004 ; Rahman et al, 2019 ). Previous studies have suggested that both Nrg1 and Nrg3 are homogeneously distributed in the same subcellular compartments.…”

Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3

“…The NRG/ErbB signaling pathway has been implicated in numerous aspects of neural development, and genetic variants of NRG1 and ERBB4 have been associated with risk for psychiatric disorders, especially schizophrenia ( Buonanno and Fischbach, 2001 ; Falls, 2003 ; Mei and Nave, 2014 ). Although NRG3 is the most widely expressed NRG throughout central nervous system (CNS) development ( Longart et al, 2004 ; Rahman et al, 2019 ; Zhang et al, 1997 ), only recently have its processing, subcellular distribution, functions in CNS neurons, and association with disease begun to be investigated. Processes regulated by NRG3 include interneuron migration ( Bartolini et al, 2017 ) and neurite outgrowth ( Rahman-Enyart et al, 2020 ), neuronal and oligodendrocyte survival ( Carteron et al, 2006 ), glutamatergic transmission ( Wang et al, 2018 ), and synapse formation/maturation onto ErbB4+ GABAergic interneurons ( Exposito-Alonso et al, 2020 ; Müller et al, 2018 ; Vullhorst et al, 2017 ).…”