Norton N, Moskvina V, Morris DW, Bray NJ, Zammit S, Williams NM, Williams HJ, Preece AC, Dwyer S, Wilkinson JC, Spurlock G, Kirov G, Buckland P, Waddington JL, Gill M, Corvin AP, Owen MJ, O'Donovan MC.
Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. Am J Med Genet B Neuropsychiatr Genet.
2006 Jan 5
Comments on News and Primary Papers
Comment by: Amanda Jayne Law, SRF Advisor
Submitted 22 February 2006
Posted 22 February 2006
I recommend the Primary Papers
The study of Ghashghaei and colleagues provides a remarkable insight into the function of neuregulin 1 (NRG1), and NRG2 in adult neurogenesis. The study demonstrates that NRG1(2)/ErbB4 signaling influences the proliferation, differentiation, organization, and migration of adult neural progenitor cells in the subventricular zone (SVZ) and rostral migratory stream (RMS), in a ligand- and cell-dependent fashion. Using immunohistochemistry, Ghashghaei and colleagues first demonstrate that NRG1, NRG2, and ErbB4 are expressed by distinct cell types in the SVZ and RMS, notably ErbB4 and NRG1 by polysialylated neural cell adhesion molecule positive (PSA-NCAM+) neuroblasts, and ErbB2/3/4 by a subset of GFAP+ cells. These observations extend the group's previous studies of NRG1 and ErbB4 in the RMS (Anton et al., 2004). In their current study, Ghashghaei went on to examine the effects of exogenous infusion of NRG1 and NRG2 on neurogenesis in the RMS of adult mice. Interestingly, NRG1 was shown to decrease the initiation of neuroblast migration from the SVZ to the RMS by inducing the rapid aggregation of cells in the SVZ. The consequence of this rise in NRG1 was a decrease in the number of PSA-NCAM+ cells in the RMS and GABA+ cells in the olfactory bulb, demonstrating that ectopic or elevated expression of NRG1 prevents differentiation and migration of neurons from the adult SVZ to the RMS.
The study is particularly interesting in terms of the role of NRG1/ErbB4 signaling in directional cell migration. Flames et al. (2004) recently reported that NRG1 (specifically the Ig containing family of isoforms, e.g., Types I, II and IV; for review, see Harrison and Law, 2006) functions as a long distance chemoattractant for ErbB4 positive GABAergic interneurons migrating from the medial ganglionic eminence to the developing cortex. The observation that NRG1 is a chemoattractant in other brain regions may appear somewhat contradictory to the findings of Ghashghaei, which suggest that in-vivo NRG1 actually inhibits migration of neurons from the SVZ (at least when introduced ectopically). However, it would seem that these two findings are actually consistent. Ghashghaei and colleagues ectopically infused NRG1 into the lateral ventricles of adult mice. The subsequent aggregation of cells in the SVZ demonstrates that NRG1 indeed acts as a chemoattractant, not in an obvious manner by inducing the cells to migrate away, but simply by "attracting" them to aggregate or "clump" where they are (subsequently preventing migration to the RMS). So in fact, both the studies of Flames and Ghashghaei show that NRG1 is chemotactic to specific populations of neurons and cells, whether it is expressed at a distance and cells preferentially migrate toward it, or in the immediate environment and cells are attracted to migrate to, or stay in its vicinity.
In the past few years, NRG1 and ErbB4 have both been identified as potential susceptibility genes for schizophrenia. The aim now is to determine the molecular and biological mechanisms by which the genes confer risk for the disease. In terms of schizophrenia, we have previously demonstrated that the Type I isoform of NRG1 is elevated in the hippocampus (and prefrontal cortex; see Hashimoto et al., 2004) in the disease and that expression of the novel Type IV isoform is related to disease-associated sequence variants within the NRG1 gene (Law et al., 2006). Furthermore, we have recently demonstrated that these changes are accompanied by altered expression of specific isoforms of the ErbB4 receptor, consistent with that of Silberberg et al., 2006 (Law et al., 2005). Ghashghaei and colleagues provide the first direct evidence that ectopic or elevated expression of NRG1 in the brain can perturb cell migration. In light of this and other evidence, our findings in schizophrenia may translate into altered neuronal migration, cortical development and possibly neurogenesis in the disease.
At present, the exact links between altered NRG1/ErbB4 signaling and the pathophysiology of schizophrenia are unknown and potentially numerous (i.e., synaptogenesis, neurotransmitter function, neuronal migration, differentiation, glia formation and function, myelination). Studies such as that of Ghashghaei et al. provide insight into the normal role of NRG1/ErbB4 signaling in neurodevelopment and the adult brain which is essential if we are to understand the pathogenic role of the NRG1 gene and its receptors in disease.
Anton ES, Ghashghaei HT, Weber JL, McCann C, Fischer TM, Cheung ID, Gassmann M, Messing A, Klein R, Schwab MH, Lloyd KC, Lai C. Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain.
Nat Neurosci. 2004 Dec;7(12):1319-28. Epub 2004 Nov 7.
Flames N, Long JE, Garratt AN, Fischer TM, Gassmann M, Birchmeier C, Lai C, Rubenstein JL, Marin O. Short- and long-range attraction of cortical GABAergic interneurons by neuregulin-1.
Neuron. 2004 Oct 14;44(2):251-61.
Hashimoto et al., 2004, Mol. Psychiatry 9, 299-307.
Law et al (a) 2006. Neuregulin 1 (NRG1) transcripts are differentially expressed in schizophrenia and regulated by 5’ SNPs associated with the disease. PNAS
Also See SfN 2005 SRF research news: Cortical Deficits in Schizophrenia: Have Genes, Will Hypothesize
Law 2005, SNPing away at NRG1 and ErbB4 gene expression in schizophrenia
Neuropsychopharmacology, vol. 30, Supplement 1.
View all comments by Amanda Jayne Law