Adult Upper Cortical Layer Specific Transcription Factor CUX2 Is Expressed in Transient Subplate and Marginal Zone Neurons of the Developing Human Brain

Abstract

Cut-Like Homeobox 2 (Cux2) is a transcription factor involved in dendrite and spine development, and synapse formation of projection neurons placed in mouse upper neocortical layers. Therefore, Cux2 is often used as an upper layer marker in the mouse brain. However, expression of its orthologue CUX2 remains unexplored in the human fetal neocortex. Here, we show that CUX2 protein is expressed in transient compartments of developing neocortical anlage during the main fetal phases of neocortical laminar development in human brain. During the early fetal phase when neurons of the upper cortical layers are still radially migrating to reach their final place in the cortical anlage, CUX2 was expressed in the marginal zone (MZ), deep cortical plate, and pre-subplate. During midgestation, CUX2 was still expressed in the migrating upper cortical neurons as well as in the subplate (SP) and MZ neurons. At the term age, CUX2 was expressed in the gyral white matter along with its expected expression in the upper layer neurons. In sum, CUX2 was expressed in migratory neurons of prospective superficial layers and in the diverse subpopulation of transient postmigratory SP and MZ neurons. Therefore, our findings indicate that CUX2 is a novel marker of distinct transient, but critical histogenetic events during corticogenesis. Given the Cux2 functions reported in animal models, our data further suggest that the expression of CUX2 in postmigratory SP and MZ neurons is associated with their unique dendritic and synaptogenesis characteristics.

Cortical Layer Markers Expression and Increased Synaptic Density in Interstitial Neurons of the White Matter from Drug-Resistant Epilepsy Patients

“…Embryonic birth-dating lineage tracing in monkeys and carnivores suggested that interstitial neurons shared the same developmental origin with subplate neurons and deep-layer cortical neurons [ 11 , 14 , 15 ]. The expression of cortical layer markers CUX2, TLE4, and FOXP1 were identified in the embryonic human subplate [ 30 ], these neurons were considered as immature migratory neurons that co-expressed with DCX [ 31 ]. However, whether interstitial neurons in the adult human brain expressed cortical neuronal markers remains unexplored.…”

Effects of chronic exposure to fluoxetine, eicosapentaenoic acid, and lipopolysaccharide on behavior and hippocampal transcriptome in the rat model of prolonged chronic unpredictable stress

“…Fluoxetine+EPA rats upregulated brain Superoxide Dismutase 3 ( Sod3 ) gene, involved in anti-inflammation and neuroprotection in stress 148 . In addition, both fluoxetine and its combination with EPA reduced the expression of Cut Like Homeobox 2 ( Cux2; vs. stress) that regulates the development of dendrites, dendritic spines and synapses of neocortical neurons in mice, and has been linked to clinical affective disorders and schizophrenia 149,150 .…”

“…As both drugs treat clinical depression, and their combination is more efficient than monotherapy 152,153 , rats treated with fluoxetine+EPA show upregulated brain Superoxide Dismutase 3 ( Sod3 ) gene involved in anti-inflammation and neuroprotection in stress 154 . Both fluoxetine and fluoxetine+EPA reduced hippocampal expression of Cut Like Homeobox 2 ( Cux2) that regulates the development of dendrites, dendritic spines and synapses of neocortical neurons in mice, and has been linked to clinical affective disorders and schizophrenia 155,156 . Unlike EPA, LPS initiates an inflammatory response via both immune and non-immune factors 123 .…”

Editorial: The earliest-born cortical neurons as multi-tasking pioneers: expanding roles for subplate neurons in cerebral cortex organization and function, volume II

“…In the fetal cortex, during mid-gestation, the subplate becomes elaborated with three sublayers and more than twice as thick as the cortical plate above it (Kostović et al, 2019 ). Molecular (Miškić et al, 2021 ; Smith et al, 2021 ; Žunić Išasegi et al, 2022 ; Junaković et al, 2023 ; Kopić et al, 2023 ) and in utero functional MRI studies described temporal changes of cellular components and morphological dynamics of the three-layered subplate (Vasung et al, 2021 ; Taymourtash et al, 2023 ; Wilson et al, 2023 ). Another focus in the research field is implication of the subplate in disease conditions.…”