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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.

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Ulk4 knockdown inhibits proliferation of cortical neural stem cells but does not change cell fate determination.(A) Both shRNA268 and 269 inhibit the proliferation of neural precursors. *p < 0.05, **p < 0.01. Error bars indicate mean ± SD. (B–D) The majority of the “trapped” GFP neurons, if not all, in the deeper layers of knockdown brains still express Satb2 (B, white arrows), instead of Ctip2 (C, white arrowheads) and Tbr1(D, white arrowheads). Bars = 20 μm.
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f3: Ulk4 knockdown inhibits proliferation of cortical neural stem cells but does not change cell fate determination.(A) Both shRNA268 and 269 inhibit the proliferation of neural precursors. *p < 0.05, **p < 0.01. Error bars indicate mean ± SD. (B–D) The majority of the “trapped” GFP neurons, if not all, in the deeper layers of knockdown brains still express Satb2 (B, white arrows), instead of Ctip2 (C, white arrowheads) and Tbr1(D, white arrowheads). Bars = 20 μm.

Mentions: Panels of plasmids containing shRNA268 or 269 together with GFP were injected into lateral ventricles of E15.5 mouse brains prior to in utero electroporation. The embryonic brains were collected on the next day (E16.5) one hour after BrdU pulse injection. Immunostaining with anti-Ulk4 antibody demonstrated a successful Ulk4 targeting (Supplementary Fig. S3). To estimate the proportion of transfected cells in S phase, immunostaining with anti-BrdU (Supplementary Fig. S4) was performed and the number of GFP/BrdU double-labelled cells was counted. The expression ratio was calculated by normalization against the total number of GFP-containing cells. Our results suggest that both Ulk4 shRNA268 group (n = 3, p < 0.02) and 269 group (n = 3, p < 0.001) have a significantly lower percentage of GFP/BrdU double-labelled cells compared with control group (n = 4) (Fig. 3A). These results strongly indicate that silencing Ulk4 in the developing brain significantly inhibits neural progenitor proliferation.


Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia
Ulk4 knockdown inhibits proliferation of cortical neural stem cells but does not change cell fate determination.(A) Both shRNA268 and 269 inhibit the proliferation of neural precursors. *p < 0.05, **p < 0.01. Error bars indicate mean ± SD. (B–D) The majority of the “trapped” GFP neurons, if not all, in the deeper layers of knockdown brains still express Satb2 (B, white arrows), instead of Ctip2 (C, white arrowheads) and Tbr1(D, white arrowheads). Bars = 20 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Ulk4 knockdown inhibits proliferation of cortical neural stem cells but does not change cell fate determination.(A) Both shRNA268 and 269 inhibit the proliferation of neural precursors. *p < 0.05, **p < 0.01. Error bars indicate mean ± SD. (B–D) The majority of the “trapped” GFP neurons, if not all, in the deeper layers of knockdown brains still express Satb2 (B, white arrows), instead of Ctip2 (C, white arrowheads) and Tbr1(D, white arrowheads). Bars = 20 μm.
Mentions: Panels of plasmids containing shRNA268 or 269 together with GFP were injected into lateral ventricles of E15.5 mouse brains prior to in utero electroporation. The embryonic brains were collected on the next day (E16.5) one hour after BrdU pulse injection. Immunostaining with anti-Ulk4 antibody demonstrated a successful Ulk4 targeting (Supplementary Fig. S3). To estimate the proportion of transfected cells in S phase, immunostaining with anti-BrdU (Supplementary Fig. S4) was performed and the number of GFP/BrdU double-labelled cells was counted. The expression ratio was calculated by normalization against the total number of GFP-containing cells. Our results suggest that both Ulk4 shRNA268 group (n = 3, p < 0.02) and 269 group (n = 3, p < 0.001) have a significantly lower percentage of GFP/BrdU double-labelled cells compared with control group (n = 4) (Fig. 3A). These results strongly indicate that silencing Ulk4 in the developing brain significantly inhibits neural progenitor proliferation.

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.


Related in: MedlinePlus