Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade.
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 beta-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.
Seshadri
Saurav
S
Departments of Psychiatry, Neuroscience, and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Kamiya
Atsushi
A
Yokota
Yukako
Y
Prikulis
Ingrid
I
Kano
Shin-ichi
S
Hayashi-Takagi
Akiko
A
Stanco
Amelia
A
Eom
Tae-Yeon
TY
Rao
Sarada
S
Ishizuka
Koko
K
Wong
Philip
P
Korth
Carsten
C
Anton
E S
ES
Sawa
Akira
A
D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000209:etiology; D015398:Signal Transduction
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D011994:Recombinant Proteins; C412476:DISC1 protein, human; C498795:Disc1 protein, rat; C094131:NRG1 protein, human; C490581:Nrg1 protein, mouse; C490580:Nrg1 protein, rat; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; C509281:Bace1 protein, rat