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Annotation

Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Hayashi-Takagi A, Stanco A, Eom TY, Rao S, Ishizuka K, Wong P, Korth C, Anton ES, Sawa A. Disrupted-in-Schizophrenia-1 expression is regulated by beta-site amyloid precursor protein cleaving enzyme-1-neuregulin cascade. Proc Natl Acad Sci U S A . 2010 Mar 23 ; 107(12):5622-7. PubMed Abstract

Comments on Paper and Primary News
Primary News: Convergence Zone: NRG1 Signaling Linked to DISC1 Expression

Comment by:  Amanda Jayne Law, SRF Advisor
Submitted 19 April 2010 Posted 19 April 2010

The study of Seshadri, Sawa, and colleagues presents novel evidence of a potential biological link between two lead schizophrenia susceptibility genes, NRG1 and DISC1. The principal finding of the study is that NRG1 (EGFβ) regulates expression of a specific isoform of DISC1, mediated via ErbB2/3 but not ErbB4. The influence of NRG1 on expression of the DISC1 isoform was confirmed in a variety of in-vitro and in-vivo models. Specifically, the authors report (using Western blotting with the DISC1 antibodies: D27 and mExon3), that treatment with NRG1 (and NRG2), but not NRG3, increases levels of DISC1 immunoreactivity at 130 kDa in immature and mature rat primary neuron cultures. Interestingly, NRG1 (or NRG2) had no effect on expression of the previously reported full-length DISC1 immunoreactive bands of 100-105 kDa. Convincingly, reduction of the 130 kDa DISC1 band was observed in BACE1 -/- and NRG1 +/- mice, both of which have reduced NRG1 signaling. Taken together, these findings suggest that NRG1 signaling regulates expression of a unique 130 kDa DISC1 protein.

This...  Read more


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Primary News: Convergence Zone: NRG1 Signaling Linked to DISC1 Expression

Comment by:  Alexander Arguello
Submitted 3 May 2010 Posted 3 May 2010

This paper raises an interesting issue. It is unclear how an immuno band that has no DISC1 sequences can result from "alternative splicing or post-translational modification." Could someone provide a mechanistic account, at the molecular level, of how this may be possible? To support that this band is DISC1, at least some DISC1 sequence should have been detected. This issue could be related to the non-specific cross-reactivity of many DISC1 antibodies (see Kvajo et al., 2008 for a discussion) and now also raises the possibility of off-target effects of DISC1 RNAi.

Resolving these issues will be paramount for making meaningful insights into how variations in DISC1 contribute to psychotic disorders.

References:

Kvajo M, McKellar H, Arguello PA, Drew LJ, Moore H, MacDermott AB, Karayiorgou M, Gogos JA. A mutation in mouse Disc1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. Proc Natl Acad Sci U S A. 2008 May 13;105(19):7076-81. Abstract

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Primary News: Convergence Zone: NRG1 Signaling Linked to DISC1 Expression

Comment by:  Saurav SeshadriAtsushi KamiyaEva AntonAkira Sawa (SRF Advisor)
Submitted 4 May 2010 Posted 4 May 2010

We are very glad to see Dr. Law’s thoughtful and very supportive comments on the work by Seshadri et al. We share the recognition, as we pointed out in the discussion of the paper, that identification of 130 kDa signal at the molecular level is an important future question. To confirm the authenticity of immunoreactivity, we tested if the 130 kDa signal is immunoprecipitated and immunoblotted by different DISC1 antibodies. Similar immunoreactive approaches have been used earlier to distinguish DISC1 isoforms, including a 71 kDa isoform in association with PDE4 (Millar et al., 2005; Chubb et al., 2008). Knockout mice deficient in DISC1 that we have recently generated (unpublished) were used for evaluating the specificity of several antibodies against DISC1 (Schurov et al., 2004; Ishizuka et al., 2007; Duan et al., 2007;   Read more


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