Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia.
In recent years evidence has accumulated that the activity of the signaling cascades of Neuregulin-1, Wnt, TGF-beta, BDNF-p75 and DISC1 is different between control subjects and patients with schizophrenia. These pathways are involved in embryonic and adult neurogenesis and neuronal maturation. A review of the clinical data indicates that in schizophrenia the Wnt pathway is most likely hypoactive, whereas the Nrg1-ErbB4, the TGF-beta- and the BDNF-p75-pathways are hyperactive. Haplo-insuffiency of the DISC1 gene is currently the best established schizophrenia risk factor. Preclinical experiments indicate that suppression of DISC1 signaling leads to accelerated dendrite development in neuronal stem cells, accelerated migration and aberrant integration into the neuronal network. Other preclinical experiments show that increasing NRG1-, BDNF- and TGF-beta signaling and decreasing Wnt signaling, also promotes adult neuronal differentiation and migration. Thus deviations in these pathways detected in schizophrenia could contribute to premature neuronal differentiation, accelerated migration and inappropriate insertion into the neuronal network. Initial clinical findings are confirmatory: neuronal stem cells isolated from nasal biopsies from schizophrenia patients display signs of accelerated development, whilst increased erosion of telomeres and bone age provide further support for accelerated cell maturation in schizophrenia.
Kalkman
Hans O
HO
Novartis Pharma AG, Novartis Institutes of Biomedical Research Basel, WSJ-386.11.40, Postfach, CH-4002 Basel, Switzerland. hans.kalkman@novartis.com
D000365:Age Determination by Skeleton; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D020890:Neuregulin-1; D055495:Neurogenesis; D066247:Receptor, ErbB-4; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012307:Risk Factors; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D016615:Telomere; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; C412476:DISC1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C484065:NGFR protein, human; C094131:NRG1 protein, human; D009419:Nerve Tissue Proteins; D020890:Neuregulin-1; D017475:Receptors, Nerve Growth Factor; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4