Disrupted-in-Schizophrenia-1 expression is regulated by β-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade

Saurav Seshadri, Atsushi Kamiya, Yukako Yokota, Ingrid Prikulis, Shin Ichi Kano, Akiko Hayashi-Takagi, Amelia Stanco, Tae Yeon Eom, Sarada Rao, Koko Ishizuka, Philip Wong, Carsten Korth, E. S. Anton, Akira Sawa

Research output: Contribution to journalArticle

Abstract

Neuregulin-1 (NRG1) and Disrupted-in-Schizophrenia-1 (DISC1) are promising susceptibility factors for schizophrenia. Both are multifunctional proteins with roles in a variety of neurodevelopmental processes, including progenitor cell proliferation, migration, and differentiation. Here, we provide evidence linking these factors together in a single pathway, which is mediated by ErbB receptors and PI3K/Akt. We show that signaling by NRG1 and NRG2, but not NRG3, increase expression of an isoform of DISC1 in vitro. Receptors ErbB2 and ErbB3, but not ErbB4, are responsible for transducing this effect, and PI3K/Akt signaling is also required. In NRG1 knockout mice, this DISC1 isoform is selectively reduced during neurodevelopment. Furthermore, a similar decrease in DISC1 expression is seen in β-site amyloid precursor protein cleaving enzyme-1 (BACE1) knockout mice, in which NRG1/Akt signaling is reportedly impaired. In contrast to neuronal DISC1 that was reported and characterized, expression of DISC1 in other types of cells in the brain has not been addressed. Here we demonstrate that DISC1, like NRG and ErbB proteins, is expressed in neurons, astrocytes, oligodendrocytes, microglia, and radial progenitors. These findings may connect NRG1, ErbBs, Akt, and DISC1 in a common pathway, which may regulate neurodevelopment and contribute to susceptibility to schizophrenia.

Original languageEnglish (US)
Pages (from-to)5622-5627
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number12
DOIs
StatePublished - Mar 23 2010

ASJC Scopus subject areas

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