Neocortex

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. Schizophrenia is a chronic and disabling brain disorder with a life time risk around 1%. It is among the top 10 causes of human disability worldwide. The causes are highly variable with both genetic and environmental factors predisposing to overall risk. Although heritability is estimated at between 60–80%, the genetic architecture and the molecular mechanisms remain controversial. Current treatments are palliative and do not alter overall prognosis. Although schizophrenia normally presents in early adult life, overwhelming evidence indicates that it has a strong neurodevelopmental component 1,2. 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 therefore interfere with brain maturation and integrity 3. The neurodevelopmental model is based on rapidly growing knowledge from animal models 4 , environmental interactions 5 and clinical findings including pre-existing morphological abnormalities in the brains of schizophrenia cases 6 and behavioural changes in childhood before the onset of symptoms 7,8. It is essential to dissect out how genetic alterations predisposing to schizophrenia alter brain development and synaptic connectivity in order to understand the underlying pathogenesis. Unfortunately, despite large numbers of susceptibility genes having been proposed, only a small proportion of the overall genetic risk has been implicated robustly in human patients either by enrichment of rare gene copy number variations, or through genome-wide significant associations of common genetic variants 9–11. Given the polygenic nature of schizophre-nia, it is possible that manifestation of this condition represents the end point of many parallel and/or convergent pathogenic processes. Many more causative genes will need to be found and their underlying mechanisms understood before it will be possible to use genetics clinically to aid diagnosis and to partition people at risk for early prevention and for stratified therapy.