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

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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.


Expression profile of Ulk4 mRNA in mouse cortex.(A) Strong in situ hybridization signals were detected broadly in the whole E12.5 cortex. (B) In E15.5 cortex, Ulk4 mRNA was expressed highly in ventricular zone, subventricular zone and cortical plate. (C) Enlarged view of the boxed region in (B). (D) Ulk4 mRNA was expressed widely in E17.5 cortex, with a preferable location in upper layers. (E,F) Similar to the expression profile of E17.5 cortex, Ulk4 mRNA was expressed extensively in the cortex at postnatal day 7 and 4 month with a predominant location in layers II–IV. cc, corpus callosum; VZ, ventricular zone; SVZ, subventricular zone; IZ; intermediate zone; CP, cortical plate; MZ, marginal zone. I–VI, sublayers of cortex. Bars = 100 μm in (B,E,F) and 20 μm in (A,C,D).
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f1: Expression profile of Ulk4 mRNA in mouse cortex.(A) Strong in situ hybridization signals were detected broadly in the whole E12.5 cortex. (B) In E15.5 cortex, Ulk4 mRNA was expressed highly in ventricular zone, subventricular zone and cortical plate. (C) Enlarged view of the boxed region in (B). (D) Ulk4 mRNA was expressed widely in E17.5 cortex, with a preferable location in upper layers. (E,F) Similar to the expression profile of E17.5 cortex, Ulk4 mRNA was expressed extensively in the cortex at postnatal day 7 and 4 month with a predominant location in layers II–IV. cc, corpus callosum; VZ, ventricular zone; SVZ, subventricular zone; IZ; intermediate zone; CP, cortical plate; MZ, marginal zone. I–VI, sublayers of cortex. Bars = 100 μm in (B,E,F) and 20 μm in (A,C,D).

Mentions: Previously, we reported abundant neuronal expression of ULK4 protein in adult human and mouse brains by immunohistochemistry12. To understand further the precise function of Ulk4 in cortical development, we synthesized specific riboprobes and performed in situ hybridization in both embryonic and postnatal mouse brains. Ulk4 transcripts were detected widely in the E12.5 cortex, when active cortical neurogenesis takes place and brain lamination arises (Fig. 1A). In E15.5 cortex, abundant hybridization signals were observed in the ventricular zone (VZ), subventricular zone (SVZ) and cortical plate, but only a weak signal was evident in the intermediate zone (Fig. 1B,C). This distribution pattern highlights the potential regulatory roles of Ulk4 in both neural progenitors and post-mitotic neurons which have exited the cell cycle and initiate migration and differentiation. In E17.5 cortex, dense hybridization signals were located in cortical plate (CP) and were more prominent than in the intermediate zone and SVZ/VZ regions (Fig. 1D). At postnatal day 7, Ulk4 transcripts were distributed extensively in all cortical layers (Fig. 1E) and in adulthood (Fig. 1F), which mirrors our previous immunohistochemical findings12. Hybridization with sense probes also was carried out and no specific signals were detected (Supplementary Fig. S1). These results show wide and dynamic Ulk4 expression in both developing and postnatal cortex which strongly supports a modulatory role of Ulk4 in corticogenesis and functional maturation.


Control of cortex development by ULK4, a rare risk gene for mental disorders including schizophrenia
Expression profile of Ulk4 mRNA in mouse cortex.(A) Strong in situ hybridization signals were detected broadly in the whole E12.5 cortex. (B) In E15.5 cortex, Ulk4 mRNA was expressed highly in ventricular zone, subventricular zone and cortical plate. (C) Enlarged view of the boxed region in (B). (D) Ulk4 mRNA was expressed widely in E17.5 cortex, with a preferable location in upper layers. (E,F) Similar to the expression profile of E17.5 cortex, Ulk4 mRNA was expressed extensively in the cortex at postnatal day 7 and 4 month with a predominant location in layers II–IV. cc, corpus callosum; VZ, ventricular zone; SVZ, subventricular zone; IZ; intermediate zone; CP, cortical plate; MZ, marginal zone. I–VI, sublayers of cortex. Bars = 100 μm in (B,E,F) and 20 μm in (A,C,D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f1: Expression profile of Ulk4 mRNA in mouse cortex.(A) Strong in situ hybridization signals were detected broadly in the whole E12.5 cortex. (B) In E15.5 cortex, Ulk4 mRNA was expressed highly in ventricular zone, subventricular zone and cortical plate. (C) Enlarged view of the boxed region in (B). (D) Ulk4 mRNA was expressed widely in E17.5 cortex, with a preferable location in upper layers. (E,F) Similar to the expression profile of E17.5 cortex, Ulk4 mRNA was expressed extensively in the cortex at postnatal day 7 and 4 month with a predominant location in layers II–IV. cc, corpus callosum; VZ, ventricular zone; SVZ, subventricular zone; IZ; intermediate zone; CP, cortical plate; MZ, marginal zone. I–VI, sublayers of cortex. Bars = 100 μm in (B,E,F) and 20 μm in (A,C,D).
Mentions: Previously, we reported abundant neuronal expression of ULK4 protein in adult human and mouse brains by immunohistochemistry12. To understand further the precise function of Ulk4 in cortical development, we synthesized specific riboprobes and performed in situ hybridization in both embryonic and postnatal mouse brains. Ulk4 transcripts were detected widely in the E12.5 cortex, when active cortical neurogenesis takes place and brain lamination arises (Fig. 1A). In E15.5 cortex, abundant hybridization signals were observed in the ventricular zone (VZ), subventricular zone (SVZ) and cortical plate, but only a weak signal was evident in the intermediate zone (Fig. 1B,C). This distribution pattern highlights the potential regulatory roles of Ulk4 in both neural progenitors and post-mitotic neurons which have exited the cell cycle and initiate migration and differentiation. In E17.5 cortex, dense hybridization signals were located in cortical plate (CP) and were more prominent than in the intermediate zone and SVZ/VZ regions (Fig. 1D). At postnatal day 7, Ulk4 transcripts were distributed extensively in all cortical layers (Fig. 1E) and in adulthood (Fig. 1F), which mirrors our previous immunohistochemical findings12. Hybridization with sense probes also was carried out and no specific signals were detected (Supplementary Fig. S1). These results show wide and dynamic Ulk4 expression in both developing and postnatal cortex which strongly supports a modulatory role of Ulk4 in corticogenesis and functional maturation.

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.