Abstract
Schizophrenia (SCZ) is a chronic and severe mental disease that affects around 1% of the population. The precise etiology of SCZ still remains largely unknown, and no conclusive mechanisms are firmly established. Recent advances in epidemiological and clinical investigation support an overwhelmingly strong neurodevelopmental origin for SCZ. Here, we demonstrated that Unc-51-like kinase 4 (Ulk4), a novel risk factor for major mental disorders including schizophrenia, is involved in the corticogenesis. Deletion of Ulk4 in mice led to significantly thinner layers of II–III, and V in the cerebral cortex, which was confirmed in conditional Ulk4 deletion mice achieved by Cre-loxp strategy. This abnormality might be caused by decreased intermediate neural progenitors and increased apoptosis. Thus, our data suggest that Ulk4 manipulates the behaviors of neural progenitors during brain development and, when functionally defective, leads to the reduction of specific cortical layers. This anomaly may increase predisposition to a range of neurodevelopmental disorders, including SCZ.
Highlights
Schizophrenia (SCZ) is a devastating brain disorder that affects approximately 1% of the population worldwide
Our results showed that the messenger RNA (mRNA) abundance of exon 1 was comparable between the control and hypomorph mice (Figure 1B), whereas exon 15 mRNA abundance was sharply reduced by 90% in homozygotes (p < 0.001; Figure 1C) compared with that in control mice
We performed immunostaining in P0 mouse brains and found that Unc-51-like kinase 4 (Ulk4) was strongly expressed in the cortex with relatively high intensity in layers II–V and the hippocampus (Supplementary Figures 2A,C), including CA1, CA3, and DG at postnatal day 7 (P7) in control mice, whereas the expression was sharply decreased in Ulk4
Summary
Schizophrenia (SCZ) is a devastating brain disorder that affects approximately 1% of the population worldwide. It imposes substantial burden of morbidity and mortality and is often associated with an average 20–25 years reduction in life span. The root reasons for SCZ are complex, but heritability is considerably high (60–80%) (Camargo et al, 2007). Most of these brain-specific molecular and genetic findings, together with epidemiological evidence, all support an overwhelmingly strong neurodevelopmental origin for SCZ (Rapoport et al, 2005). It has been proposed that various genetic lesions can have detrimental effects as early as in the first or early second trimester (Fatemi and Folsom, 2009) and, as a result, can disturb the cellular architecture and synaptic connectivity of the developing brain of
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