Neuregulin 1 (Nrg1) encodes a neurotrophic factor and is genetically associated with schizophrenia, bipolar disorder and major depression. NRG1 has been shown to play important roles in neurodevelopment and neurotransmission. However, the knowledge about the cellular expression pattern of Nrg1 in mouse forebrain remains controversial and inconclusive. Here we used CRISPR/Cas9 techniques to generate Nrg1Cre/+ knockin mice which express the Cre recombinase immediately before the stop codon of Nrg1 gene. By crossing the Nrg1Cre/+ mice with Ai14 reporter mice which express fluorescent protein tdTomato in a Cre-dependent manner, we generated Nrg1 reporter mice which express tdTomato in cells where Nrg1 gene is actively transcribed. Using fluorescence imaging and unbiased stereology, we revealed the cellular expression pattern of Nrg1 in mouse forebrain regions including the olfactory bulb, cerebral cortex, striatum and hippocampus. We further performed stereotaxic injection of adeno-associated virus (AAV) which express tdTomato in a Cre-dependent way into different forebrain regions of adult Nrg1Cre/+ mice, and thus explored the distribution and axon projection of Nrg1-positive cells. These results provide fundamental information needed for the study of Nrg1 function in mouse forebrain. Moreover, the Nrg1Cre/+ mice generated here may represent a useful tool to study the function of neuronal populations expressing Nrg1.
Background Where the gene is expressed determines the function of the gene. Neuregulin 1 (Nrg1) encodes a tropic factor and is genetically linked with several neuropsychiatry diseases such as schizophrenia, bipolar disorder and depression. Nrg1 has broad functions ranging from regulating neurodevelopment to neurotransmission in the nervous system. However, the expression pattern of Nrg1 at the cellular and circuit levels in rodent brain is not full addressed. Methods Here we used CRISPR/Cas9 techniques to generate a knockin mouse line (Nrg1Cre/+) that expresses a P2A-Cre cassette right before the stop codon of Nrg1 gene. Since Cre recombinase and Nrg1 are expressed in the same types of cells in Nrg1Cre/+ mice, the Nrg1 expression pattern can be revealed through the Cre-reporting mice or adeno-associated virus (AAV) that express fluorescent proteins in a Cre-dependent way. Using unbiased stereology and fluorescence imaging, the cellular expression pattern of Nrg1 and axon projections of Nrg1-positive neurons were investigated. Results In the olfactory bulb (OB), Nrg1 is expressed in GABAergic interneurons including periglomerular (PG) and granule cells. In the cerebral cortex, Nrg1 is mainly expressed in the pyramidal neurons of superficial layers that mediate intercortical communications. In the striatum, Nrg1 is highly expressed in the Drd1-positive medium spiny neurons (MSNs) in the shell of nucleus accumbens (NAc) that project to substantia nigra pars reticulata (SNr). In the hippocampus, Nrg1 is mainly expressed in granule neurons in the dentate gyrus and pyramidal neurons in the subiculum. The Nrg1-expressing neurons in the subiculum project to retrosplenial granular cortex (RSG) and mammillary nucleus (MM). Nrg1 is highly expressed in the median eminence (ME) of hypothalamus and Purkinje cells in the cerebellum. Conclusions Nrg1 is broadly expressed in mouse brain, mainly in neurons, but has unique expression patterns in different brain regions.
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