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Bjarnadottir M, Misner DL, Haverfield-Gross S, Bruun S, Helgason VG, Stefansson H, Sigmundsson A, Firth DR, Nielsen B, Stefansdottir R. Neuregulin1 (NRG1) signaling through Fyn modulates NMDA receptor phosphorylation: Differential synaptic function in NRG+/- knock-outs compared with wild-type mice. J. Neurosci . 2007 Apr 25 ; 27():4519-4529. Abstract

Comments on Paper and Primary News
Primary News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Daniel StewartKenneth Davis
Submitted 3 May 2007 Posted 3 May 2007

Comment by Daniel Stewart and Kenneth Davis
The Corfas results are intriguing. Their findings confirm much of what we have either found or suspect in schizophrenia relating to white matter involvement. Demonstrations of OLIG2 interactions with ErbB4 in the cortex and with CNP in the striatum in schizophrenia from our team (Georgieva et al., 2006) fit well with this investigation in providing evidence for a link between a variety of potential etiologic oligodendrocyte-related mechanisms in schizophrenia. While in our study, we did not find interaction with NRG1 and OLIG2, it is important to note that differential expression of NRG1 might be found only at certain points in the timeline of disease development. Other recent support from our team for white matter involvement in schizophrenia comes from an investigation in which an SNP associated with CNP was found to be significantly correlated with schizophrenia (Peirce et al., 2006). Interestingly, Corfas’s group reports that...  Read more


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Primary News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Akira Sawa, SRF Advisor
Submitted 4 May 2007 Posted 4 May 2007

Neuregulin1 (NRG1) is the most promising risk factor for schizophrenia, and the study of the signaling of NRG1 and its receptor ErbB4 is very important in understanding the pathophysiology of the disease. Like other promising risk factors for schizophrenia, NRG1/ErbB4 is multifunctional with many molecular isoforms. NRG1/ErbB signaling plays a role both before and after birth. Furthermore, ErbB4 is expressed not only in neurons but also in other types of cells, such as oligodendrocytes.

To address context-dependent functions one by one, dominant-negative transgenic mice can be very useful. The advantage of dominant-negative transgenics is that we can knock down the endogenous function of our target molecules (in this work, ErbB4) in a temporally and spatially specific manner by utilizing a well-characterized promoter. In this outstanding study by Corfas and colleagues, they used the CNP promoter that confirms dominant-negative ErbB4 selectively in oligodendrocytes (but not in astrocytes and neurons) only after birth. This approach will be very useful in schizophrenia...  Read more


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Primary News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Mary Reid
Submitted 3 May 2007 Posted 5 May 2007

Does the effect of NRG1/ErbB4 signaling on myelination occur downstream of purinergic signaling? Fields suggests that adenosine is of primary importance in regulating early development of OPCs, where it stimulates differentiation and myelination (Fields, 2006). It's of interest that cAMP stimulates expression of neuregulin and cAMP levels in the lung are decreased in A2A adenosine receptor (22q11.2)-deficient mice (Tokita et al., 2001; Nadeem et al., 2007). Do you see reduced neuregulin levels in 22q11 deletion syndrome? Of particular interest is the study by Desai and colleagues reporting that signaling via the adenosine A2A receptor downregulates thrombospondin 1 (Desai et al., 2005). Perhaps overexpression of thrombospondin 1 may help explain the occular abnormalities in this syndrome (Wu et al., 2006; Forbes et al., 2007; Stalmans, 2005). Thrombospondins are also involved in synaptogenesis (Christopherson et al., 2005).

References:

Fields RD. Nerve impulses regulate myelination through purinergic signalling. Novartis Found Symp. 2006;276:148-58; discussion 158-61, 233-7, 275-81.

Tokita Y, Keino H, Matsui F, Aono S, Ishiguro H, Higashiyama S, Oohira A. Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J Neurosci. 2001 Feb 15;21(4):1257-64.

Nadeem A, Fan M, Ansari HR, Ledent C, Mustafa SJ. Enhanced airway reactivity and inflammation in A2A adenosine receptor deficient allergic mice. Am J Physiol Lung Cell Mol Physiol. 2007 Feb 9; [Epub ahead of print]

Desai A, Victor-Vega C, Gadangi S, Montesinos MC, Chu CC, Cronstein BN. Adenosine A2A receptor stimulation increases angiogenesis by down-regulating production of the antiangiogenic matrix protein thrombospondin 1. Mol Pharmacol. 2005 May;67(5):1406-13. Epub 2005 Jan 26. Comment in: Mol Pharmacol. 2005 May;67(5):1385-7.

Wu Z, Wang S, Sorenson CM, Sheibani N. Attenuation of retinal vascular development and neovascularization in transgenic mice over-expressing thrombospondin-1 in the lens. Dev Dyn. 2006 Jul;235(7):1908-20.

Forbes BJ, Binenbaum G, Edmond JC, Delarato N, McDonald-McGinn DM, Zackai EH. Ocular findings in the chromosome 22q11.2 deletion syndrome. J AAPOS. 2007 Apr;11(2):179-182. Epub 2006 Nov 30.

Stalmans I. Role of the vascular endothelial growth factor isoforms in retinal angiogenesis and DiGeorge syndrome. Verh K Acad Geneeskd Belg. 2005;67(4):229-76.

Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA. Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005 Feb 11;120(3):421-33. Comment in: Cell. 2005 Feb 11;120(3):292-3.

View all comments by Mary Reid


Primary News: Neuregulin and ErbB4 Mutant Mice Reveal Myelin and Synaptic Deficits

Comment by:  Patricia Estani
Submitted 6 May 2007 Posted 6 May 2007
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