Specific Regulation of NRG1 Isoform Expression by Neuronal Activity

Abstract

Neuregulin 1 (NRG1) is a trophic factor that has been implicated in neural development, neurotransmission and synaptic plasticity. NRG1 has multiple isoforms that are generated by usage of different promoters and alternative splicing of a single gene. However, little is known about NRG1 isoform composition profile, whether it changes during development or the underlying mechanisms. We found that each of the six types of NRG1 has a distinct expression pattern in the brain at different ages, resulting in a change in NRG1 isoform composition. In both human and rat, the most dominant are types III and II followed by either types I or V, while types IV and VI are the least abundant. The expression of NRG1 isoforms is higher in rat brains at ages of E13 and P5 (in particular type V), suggesting roles in early neural development and in the neonatal critical period. At the cellular level, the majority of NRG1 isoforms (types I, II and III) is expressed in excitatory neurons although they are also present in GABAergic neurons and astrocytes. Finally, the expression of each NRG1 isoform is distinctly regulated by neuronal activity, which causes significant increase in type I and IV NRG1 levels. Neuronal activity regulation of type IV expression requires a CRE cis-element in the 5′UTR that bind to CREB. These results indicate that expression of NRG1 isoforms is regulated by distinct mechanisms, which may contribute to versatile functions of NRG1 and pathologic mechanisms of brain disorders such as schizophrenia.

The Role of Neuregulin-1 In the Response To Nerve Injury

“…Isoforms differ in their N-terminal motifs, and based on these differences, NRG1 isoforms are categorized into six types, type I-VI. Functionally, the most widely studied isoform subtypes have been types I-III, while little is yet known about the more recently described types IV-VI [16][17][18].…”

“…TACE, BACE, ADAM10 and ADAM19 are all known to be capable of cleaving NRG1 isoforms. NRG1 isoform types IV, V and VI are also known to be expressed by humans and rodents; however, their function and expression patterns are as yet unknown in the PNS and consequently they have not been included in this figure [18]. Types I and II contain an Ig domain and are consequently referred to as IgNRG1s.…”

“…Isoforms differ in their N-terminal motifs, and based on these differences, NRG1 isoforms are categorized into six types, type I-VI. Functionally, the most widely studied isoform subtypes have been types I-III, while little is yet known about the more recently described types IV-VI [16][17][18].Type I, II, IV and V isoforms contain a single transmembrane domain and immunoglobulin (Ig)-like domains in their N-terminus, hence they are sometimes referred to as the Ig-NRGs. Type II isoforms also have a kringle-like domain in their N-terminus ( Figure 1).…”

NRG1 Types Down Regulate in Methamphetamine and Heroin Dependent Patients

“…Keywords: NRG1, schizophrenia, meth dependent, heroin dependent, gene expression I, II and III of NRG1 express in human peripheral blood in addition to neurons, and types IV and V expressing specifically in brain. 6 Association of several polymorphisms in NRG1 with schizophrenia, bipolar disorder and depression were reported; 7 but direction of NRG1 expression changes in schizophrenia and other behavioral characterizations are controversial. 8 Law et al 9 were reported over expression of type I and Nicodemus et al 9 were reported down expression of type III both in hippocampus of schizophrenic patients.…”

RNAscope for <em>In situ</em> Detection of Transcriptionally Active Human Papillomavirus in Head and Neck Squamous Cell Carcinoma

“…However, detection of E6/E7 mRNA from fresh tumor tissue by RT-PCR technique is not practical in routine clinical practice and has been limited to the research laboratories. Recently, we have developed a novel RNA ISH technology called RNAscope, which enables multiplex detection in individual cells with single RNA molecule sensitivity in formalin fixed paraffin embedded tissue specimens (FFPE) [5][6][7][8][9][10] . We provided three lines of evidence for single molecule detection 5 .…”