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Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia

View Article: PubMed Central - PubMed

ABSTRACT

Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia. Now using the approach of in utero gene transfer we have discovered that Ulk4 plays a key modulatory role in corticogenesis. Knockdown of Ulk4 leads to significantly decreased cell proliferation in germinal zones and profound deficits in radial migration and neurite ramification. These abnormalities can be reversed successfully by Ulk4 gene supplementation. Ulk4 also regulated acetylation of α-tubulin, an important post-translational modification of microtubules. We conclude that Ulk4 plays an essential role in normal brain development and when defective, the risk of neurodevelopmental disorders such as schizophrenia is increased.

No MeSH data available.


Validation of Ulk4 shRNA268, 269 and 270.(A) Western blotting with anti-Flag antibody shows that shRNA268 mediates the strongest knockdown of Ulk4 whilst shRNA270 displays a mild effect. (B) Normalized knockdown efficiency of the three shRNAs (n = 3 for each). *p < 0.05, **p < 0.01, two-tailed student’s t tests. Error bars indicate mean ± S.E.M.
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f2: Validation of Ulk4 shRNA268, 269 and 270.(A) Western blotting with anti-Flag antibody shows that shRNA268 mediates the strongest knockdown of Ulk4 whilst shRNA270 displays a mild effect. (B) Normalized knockdown efficiency of the three shRNAs (n = 3 for each). *p < 0.05, **p < 0.01, two-tailed student’s t tests. Error bars indicate mean ± S.E.M.

Mentions: We first tested the knockdown efficiency of Ulk4 shRNA268, 269 and 270 by co-transfection with Ulk4 full-length cDNA (tagged with c-Myc and DDK) in HEK293 cells. Two days after transfection, cells were lysed and blotted with anti-Flag. The results showed that among the three Ulk4 shRNAs, 268 presented the strongest knockdown capacity whilst 270 displayed the weakest effect (Fig. 2A,B). Blotting with anti-c-Myc also demonstrated similar knockdown capacity of the three shRNAs (Supplementary Fig. S2). Therefore, shRNA268 and 269 were chosen for functional analysis.


Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia
Validation of Ulk4 shRNA268, 269 and 270.(A) Western blotting with anti-Flag antibody shows that shRNA268 mediates the strongest knockdown of Ulk4 whilst shRNA270 displays a mild effect. (B) Normalized knockdown efficiency of the three shRNAs (n = 3 for each). *p < 0.05, **p < 0.01, two-tailed student’s t tests. Error bars indicate mean ± S.E.M.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037360&req=5

f2: Validation of Ulk4 shRNA268, 269 and 270.(A) Western blotting with anti-Flag antibody shows that shRNA268 mediates the strongest knockdown of Ulk4 whilst shRNA270 displays a mild effect. (B) Normalized knockdown efficiency of the three shRNAs (n = 3 for each). *p < 0.05, **p < 0.01, two-tailed student’s t tests. Error bars indicate mean ± S.E.M.
Mentions: We first tested the knockdown efficiency of Ulk4 shRNA268, 269 and 270 by co-transfection with Ulk4 full-length cDNA (tagged with c-Myc and DDK) in HEK293 cells. Two days after transfection, cells were lysed and blotted with anti-Flag. The results showed that among the three Ulk4 shRNAs, 268 presented the strongest knockdown capacity whilst 270 displayed the weakest effect (Fig. 2A,B). Blotting with anti-c-Myc also demonstrated similar knockdown capacity of the three shRNAs (Supplementary Fig. S2). Therefore, shRNA268 and 269 were chosen for functional analysis.

View Article: PubMed Central - PubMed

ABSTRACT

Schizophrenia is a debilitating familial neuropsychiatric disorder which affects 1% of people worldwide. Although the heritability for schizophrenia approaches 80% only a small proportion of the overall genetic risk has been accounted for, and to date only a limited number of genetic loci have been definitively implicated. We have identified recently through genetic and in vitro functional studies, a novel serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a rare risk factor for major mental disorders including schizophrenia. Now using the approach of in utero gene transfer we have discovered that Ulk4 plays a key modulatory role in corticogenesis. Knockdown of Ulk4 leads to significantly decreased cell proliferation in germinal zones and profound deficits in radial migration and neurite ramification. These abnormalities can be reversed successfully by Ulk4 gene supplementation. Ulk4 also regulated acetylation of &alpha;-tubulin, an important post-translational modification of microtubules. We conclude that Ulk4 plays an essential role in normal brain development and when defective, the risk of neurodevelopmental disorders such as schizophrenia is increased.

No MeSH data available.