Tbr1 Misexpression Alters Neuronal Development in the Cerebral Cortex

Abstract

Changes in the transcription factor (TF) expression are critical for brain development, and they may also underlie neurodevelopmental disorders. Indeed, T-box brain1 (Tbr1) is a TF crucial for the formation of neocortical layer VI, and mutations and microdeletions in that gene are associated with malformations in the human cerebral cortex, alterations that accompany autism spectrum disorder (ASD). Interestingly, Tbr1 upregulation has also been related to the occurrence of ASD-like symptoms, although limited studies have addressed the effect of increased Tbr1 levels during neocortical development. Here, we analysed the impact of Tbr1 misexpression in mouse neural progenitor cells (NPCs) at embryonic day 14.5 (E14.5), when they mainly generate neuronal layers II–IV. By E18.5, cells accumulated in the intermediate zone and in the deep cortical layers, whereas they became less abundant in the upper cortical layers. In accordance with this, the proportion of Sox5+ cells in layers V–VI increased, while that of Cux1+ cells in layers II–IV decreased. On postnatal day 7, fewer defects in migration were evident, although a higher proportion of Sox5+ cells were seen in the upper and deep layers. The abnormal neuronal migration could be partially due to the altered multipolar-bipolar neuron morphologies induced by Tbr1 misexpression, which also reduced dendrite growth and branching, and disrupted the corpus callosum. Our results indicate that Tbr1 misexpression in cortical NPCs delays or disrupts neuronal migration, neuronal specification, dendrite development and the formation of the callosal tract. Hence, genetic changes that provoke ectopic Tbr1 upregulation during development could provoke cortical brain malformations.

A selective defect in the glial wedge as part of the neuroepithelium disruption in hydrocephalus development in the mouse hyh model is associated with complete corpus callosum dysgenesis

“…Additionally, the cingulate and frontal cortices were studied by in situ hybridization for Tbr1 mRNA and Tag1 mRNA. Correct expression in cortical layers of Tbr1 is necessary for proper corpus callosum development ( Bulfone et al, 1995 ; Crespo et al, 2022 ). Tag1 protein is an axonal adhesion molecule expressed in cortical neurons projecting efferent axons, both callosal and pioneering axons ( Kastriti et al, 2019 ).…”

GSK-3β inhibitor TWS119 promotes neuronal differentiation after hypoxic-ischemic brain damage in neonatal rats

“…Cortex development occurs from inside to outside, first with the inner layers (V–VI), followed by the outer layers (II–IV). TBR1 is a key transcription factor in cerebral cortex development, mainly expressed in Cajal-Retzius cells, subplate neurons, and layer VI glutamatergic neurons [ 28 ]. So, the distribution range of TBR1-positive neurons may indicate the neuron migration and cortex development and the number of TBR1-positive neurons may indicates the development of excitatory neurons.…”

Cortical neurons obtained from patient-derived iPSCs with GNAO1 p.G203R variant show altered differentiation and functional properties

“…Indeed, variants in the FOXG1 gene have been linked to a rare form of epileptic encephalopathy (OMIM #613454) (44). TBR1 is a master regulator of cortex development that plays a crucial role in the formation of neocortical layer VI, regulating both neuronal migration and synaptic development (45;46). Pathogenic variants in TBR1 gene are associated with cortical malformations, intellectual disability and autism spectrum disorder.…”