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.
Highlights
Schizophrenia is a chronic and disabling brain disorder with a life time risk around 1%
Through a meta-analysis of several large cohorts worldwide, we reported recently a serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a novel, rare risk factor for human schizophrenia, autism and major depression[12]
ULK4 belongs to the family of unc-51-like serine/threonine kinases which participates in a conserved pathway involving both endocytosis and axon growth[13,14,15]
Summary
Schizophrenia is a chronic and disabling brain disorder with a life time risk around 1%. An increased predisposition has been shown to stem from various developmental insults that occur at first, or early second trimester of pregnancy These insults often cause molecular changes which disturb the cellular architecture and neuronal connectivity and interfere with brain maturation and integrity[3]. Through a meta-analysis of several large cohorts worldwide, we reported recently a serine/threonine kinase gene, unc-51-like kinase 4 (ULK4), as a novel, rare risk factor for human schizophrenia, autism and major depression[12]. The cells present abnormal cytoskeleton remodelling, reduced cell motility and reduced neuritogenesis[12] These findings provide the first body of mechanistic evidence which potentially associates ULK4 with mental disorders
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