Altered growth factor signaling pathways as the basis of aberrant stem cell maturation in schizophrenia

• Published in: Pharmacology & therapeutics (Oxford) Vol. 121; no. 1; pp. 115 - 122
• Main Author: Kalkman, Hans O.
• Format: Journal Article
• Language: English
• Published: England 01.01.2009
• Subjects: Age Determination by Skeleton; Animals; Brain-Derived Neurotrophic Factor - genetics; Brain-Derived Neurotrophic Factor - metabolism; Brain-Derived Neurotrophic Factor - physiology; Cell Differentiation - physiology; Humans; Intercellular Signaling Peptides and Proteins - physiology; Mice; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nerve Tissue Proteins - physiology; Neuregulin-1; Neurogenesis; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Receptor, Epidermal Growth Factor - physiology; Receptor, ErbB-4; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - metabolism; Receptors, Nerve Growth Factor - physiology; Risk Factors; Schizophrenia - metabolism; Schizophrenia - physiopathology; Signal Transduction - physiology; Stem Cells - physiology; Telomere; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Transforming Growth Factor beta - physiology; Wnt Proteins - genetics; Wnt Proteins - metabolism; Wnt Proteins - physiology
• ISSN: 0163-7258
• DOI: 10.1016/j.pharmthera.2008.11.002

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.