Ishizuka K, Kamiya A, Oh EC, Kanki H, Seshadri S, Robinson JF, Murdoch H, Dunlop AJ, Kubo K, Furukori K, Huang B, Zeledon M, Hayashi-Takagi A, Okano H, Nakajima K, Houslay MD, Katsanis N, Sawa A.
DISC1-dependent switch from progenitor proliferation to migration in the developing cortex. Nature.
2011 May 5
Comments on News and Primary Papers
Comment by: Albert H. C. Wong
Submitted 13 May 2011
Posted 13 May 2011
This recent and important paper by Sawa's group adds another layer to the complex story of DISC1 function in neurodevelopment. Their findings clarify and integrate two streams of research implicating DISC1 in both neuron proliferation and migration. The identification of the S170 phosphorylation site also raises the exciting possibility that pharmacological strategies targeted at this phosphorylation-dependent switch might be useful in correcting or preventing mental illness-related problems with brain development. It would be interesting in this context to explore whether disease-associated DISC1 gene variants in humans affect DISC1 phosphorylation, and the subsequent balance between neuron proliferation and migration.
I agree with Atsushi Kamiya that further work is needed to understand which of the many effects of DISC1 perturbation are specific to human psychiatric disease phenotypes. Again, from a treatment perspective, it is vital to know which cellular abnormality underlies the most debilitating symptoms so that new treatments can be screened for effects on these specific abnormalities. Another recent paper from our group reinforces this point (Lee et al., 2011). We found that genetic inactivation of GSK3α restored dendritic spine deficits in DISC1 L100P mutant mice, in parallel with amelioration of behavioral abnormalities as previously reported (Lipina et al., 2011). However, other abnormalities in dendrite morphology caused by the DISC1 L100P mutation were not corrected by GSK3α inactivation.
Lee FH, Kaidanovich-Beilin O, Roder JC, Woodgett JR, Wong AH. Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice, Schizophrenia Research. 2011;Apr 16. Abstract
Lipina TV, Kaidanovich-Beilin O, Patel S, Wang M, Clapcote SJ, Liu F, Woodgett JR, Roder JC. Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3. Synapse. 2011;65:234-248. Abstract
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