Neuregulin1 Nuclear Signaling Influences Adult Neurogenesis and Regulates a Schizophrenia Susceptibility Gene Network within the Mouse Dentate Gyrus.

Rajebhosale, Prithviraj; Jone, Alice; Johnson, Kory R; Hofland, Rohan; Palarpalar, Camille; Khan, Samara; Role, Lorna W; Talmage, David A

Rajebhosale, Prithviraj; Jone, Alice; Johnson, Kory R; Hofland, Rohan; Palarpalar, Camille; Khan, Samara; Role, Lorna W; Talmage, David A.

Afiliación

Rajebhosale P; Genetics of Neuronal Signaling Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Jone A; Graduate Program in Neuroscience, State University of New York at Stony Brook, Stony Brook, New York 11794.
Johnson KR; Bioinformatics Core, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 21042.
Hofland R; Undergraduate Biology, Stony Brook University, Stony Brook, New York 11794.
Palarpalar C; Undergraduate Biology, Stony Brook University, Stony Brook, New York 11794.
Khan S; Undergraduate Biology, Stony Brook University, Stony Brook, New York 11794.
Role LW; Circuits, Synapses, & Molecular Signaling Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Talmage DA; Genetics of Neuronal Signaling Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 david.talmage@nih.gov.

J Neurosci ; 44(43)2024 Oct 23.

Article en En | MEDLINE | ID: mdl-39214704

ABSTRACT

ABSTRACT

Neuregulin1 (Nrg1) signaling is critical for neuronal development and function from fate specification to synaptic plasticity. Type III Nrg1 is a synaptic protein which engages in bidirectional signaling with its receptor ErbB4. Forward signaling engages ErbB4 phosphorylation, whereas back signaling engages two known mechanisms (1) local axonal PI3K-AKT signaling and (2) cleavage by Î³-secretase resulting in cytosolic release of the intracellular domain (ICD), which can traffic to the nucleus (Bao et al., 2003; Hancock et al., 2008). To dissect the contribution of these alternate signaling strategies to neuronal development, we generated a transgenic mouse with a missense mutation (V321L) in the Nrg1 transmembrane domain that disrupts nuclear back signaling with minimal effects on forward signaling or local back signaling and was previously found to be associated with psychosis (Walss-Bass et al., 2006). We combined RNA sequencing, retroviral fate mapping of neural stem cells, behavioral analyses, and various network analyses of transcriptomic data to investigate the effect of disrupting Nrg1 nuclear back signaling in the dentate gyrus (DG) of male and female mice. The V321L mutation impairs nuclear translocation of the Nrg1 ICD and alters gene expression in the DG. V321L mice show reduced stem cell proliferation, altered cell cycle dynamics, fate specification defects, and dendritic dysmorphogenesis. Orthologs of known schizophrenia (SCZ)-susceptibility genes were dysregulated in the V321L DG. These genes coordinated a larger network with other dysregulated genes. Weighted gene correlation network analysis and protein interaction network analyses revealed striking similarity between DG transcriptomes of V321L mouse and humans with SCZ.

Asunto(s)

Giro Dentado; Redes Reguladoras de Genes; Neurregulina-1; Neurogénesis; Esquizofrenia; Transducción de Señal; Animales; Femenino; Masculino; Ratones; Núcleo Celular/metabolismo; Giro Dentado/metabolismo; Redes Reguladoras de Genes/genética; Predisposición Genética a la Enfermedad/genética; Ratones Endogámicos C57BL; Ratones Transgénicos; Mutación Missense; Células-Madre Neurales/metabolismo; Neurregulina-1/genética; Neurregulina-1/metabolismo; Neurogénesis/fisiología; Neurogénesis/genética; Esquizofrenia/genética; Esquizofrenia/metabolismo; Transducción de Señal/genética; Transducción de Señal/fisiología

Palabras clave

ErbB4; dentate gyrus; gamma secretase; neuregulin1; neurogenesis; schizophrenia

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esquizofrenia / Transducción de Señal / Giro Dentado / Neurregulina-1 / Redes Reguladoras de Genes / Neurogénesis Límite: Animals Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos

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