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

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.

Changes in the liver transcriptome of farmed Atlantic salmon (Salmo salar) fed experimental diets based on terrestrial alternatives to fish meal and fish oil

“…However, the interaction between htra1 and apoptosis may be inferred from the down-regulation of gadd45b paralogues (qPCR validated) and serine/threonine-protein kinase ULK4 (microarray identified) by VEG diet. In mammals, GADD45B and ULK4 were related to the regulation of apoptosis through p38 MAPK signaling pathways [ 102 , 103 ], pathways in cross-talk with that of TGF-beta [ 104 ]. Piscine HTRA1 would require further investigation before drawing conclusions on its significance in salmon physiology.…”

Primary Cilia–An Underexplored Topic in Major Mental Illness

“…Furthermore, CDC42 and actin skeleton remodelling have been associated with deficits in dendritic spine formation frequently reported in SCZ and BD (76–78). Issues relating to neuronal network health, such as synaptic connectivity and neurite number have also been highlighted in both mental illness and PC dysfunction (53, 54, 79–85).…”

Intragenic Microdeletion of <b><i>ULK4</i></b> and Partial Microduplication of <b><i>BRWD3</i></b> in Siblings with Neuropsychiatric Features and Obesity

“…Interestingly, studies on the expression of ULK4 in Xenopus laevis suggested a possible role of this gene during forebrain neurogenesis and its involvement in migration processes [Dominguez et al, 2015]. Furthermore, CNVs of ULK4 are considered risk factors for neurodevelopmental and neuropsychiatric disorders, as such have been described in schizophrenia and autism patients [Lang et al, 2014[Lang et al, , 2016. Proper expression of ULK4 is essential for neuritogenesis and neuronal motility, and deficiency of Ulk4 compromises the development and integrity of the corpus callosum in mice [Lang et al, 2014].…”