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Annotation

Singh KK, Ge X, Mao Y, Drane L, Meletis K, Samuels BA, Tsai LH. Dixdc1 is a critical regulator of DISC1 and embryonic cortical development. Neuron . 2010 Jul 15 ; 67(1):33-48. PubMed Abstract

Comments on Paper and Primary News
Primary News: Dynamic Duo: DISC1 and Dixdc1 Team Up to Regulate Brain Development

Comment by:  Kevin J. Mitchell
Submitted 19 July 2010 Posted 19 July 2010

The paper by Singh and colleagues adds to the growing list of proteins that interact with DISC1 and deepens our understanding of the biochemical pathways through which DISC1 modulates various neurodevelopmental processes. They demonstrate that the Dixdc1 protein interacts biochemically with DISC1, and that it functions together with DISC1 in two separable processes: neuronal proliferation and migration.

Interestingly, the nature of the interaction between Dixdc1 and DISC1 differs in these two processes. Knockdown of either Dixdc1 or DISC1 reduces proliferation, but the effects of knocking both down together are additive, indicating the absence of any epistatic interaction. Moreover, the effects of knockdown of either gene alone can be rescued by overexpressing the other gene. This suggests a partial redundancy in their functions rather than an intimate relationship where they necessarily work together.

Knockdown of either gene also disrupts neuronal migration in the cortex, but in this case the defects cannot be rescued by overexpression of the other gene, suggesting...  Read more


View all comments by Kevin J. Mitchell

Primary News: Dynamic Duo: DISC1 and Dixdc1 Team Up to Regulate Brain Development

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 July 2010 Posted 21 July 2010

The high prevalence of schizophrenia and related major mental illness, including bipolar disorder, in the Scottish family with the chromosome 1;11 translocation told us that the breakpoint gene DISC1 was an important key to unlocking the door on the molecular mechanisms underlying psychiatric illness (Millar et al., 2000; Blackwood et al., 2001). And so it has turned out to be (see review by Chubb et al., 2008). DISC1 is a scaffold protein that binds to and regulates other proteins critical in neurodevelopment and neurosignaling. We know the identity of several DISC1 interactors—PDE4, NDE1, NDEL1, PCM1, and Girdin amongst them—but at every turn, a new interactor seems to turn up.

Just last year, Li-Huei Tsai’s group identified GSK3β as a fascinating addition to the pantheon (Mao et al., 2009). GSK3β is interesting on two major counts: first, for its role in Wnt...  Read more


View all comments by David J. Porteous

Primary News: Dynamic Duo: DISC1 and Dixdc1 Team Up to Regulate Brain Development

Comment by:  Fengquan Zhou
Submitted 3 August 2010 Posted 3 August 2010
  I recommend this paper

Last year, an interesting paper (Mao et al., 2009) demonstrated that DISC1 regulates neurogenesis via directly interacting with and inhibiting GSK3, which subsequently activates the canonical Wnt pathway via stabilization of β-cantenin. Now a paper from the same group has identified a DISC1 binding protein named Dixdc1, which functions together with DISC1 to regulate neurogenesis and neuronal migration.

Specifically, the paper demonstrates that knocking down either DISC1 or Dixdc1 impairs neural progenitor proliferation and the activation of the canonical Wnt pathway, and double knocking down both proteins has an additive effect. In addition, the effects of knockdown of either gene alone can be fully rescued by overexpressing the other gene. These results suggest that DISC1 and Dixdc1 play redundant roles in regulation of neural progenitor cell proliferation via the GSK3-β-catenin pathway. However, disruption of the interaction between the two proteins also decreases the progenitor proliferation and the activation of...  Read more


View all comments by Fengquan Zhou
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