Structural and Functional Aspects of the Neurodevelopmental Gene NR2F1: From Animal Models to Human Pathology

Abstract

The assembly and maturation of the mammalian brain result from an intricate cascade of highly coordinated developmental events, such as cell proliferation, migration, and differentiation. Any impairment of this delicate multi-factorial process can lead to complex neurodevelopmental diseases, sharing common pathogenic mechanisms and molecular pathways resulting in multiple clinical signs. A recently described monogenic neurodevelopmental syndrome named Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) is caused by NR2F1 haploinsufficiency. The NR2F1 gene, coding for a transcriptional regulator belonging to the steroid/thyroid hormone receptor superfamily, is known to play key roles in several brain developmental processes, from proliferation and differentiation of neural progenitors to migration and identity acquisition of neocortical neurons. In a clinical context, the disruption of these cellular processes could underlie the pathogenesis of several symptoms affecting BBSOAS patients, such as intellectual disability, visual impairment, epilepsy, and autistic traits. In this review, we will introduce NR2F1 protein structure, molecular functioning, and expression profile in the developing mouse brain. Then, we will focus on Nr2f1 several functions during cortical development, from neocortical area and cell-type specification to maturation of network activity, hippocampal development governing learning behaviors, assembly of the visual system, and finally establishment of cortico-spinal descending tracts regulating motor execution. Whenever possible, we will link experimental findings in animal or cellular models to corresponding features of the human pathology. Finally, we will highlight some of the unresolved questions on the diverse functions played by Nr2f1 during brain development, in order to propose future research directions. All in all, we believe that understanding BBSOAS mechanisms will contribute to further unveiling pathophysiological mechanisms shared by several neurodevelopmental disorders and eventually lead to effective treatments.

Developmental cell death of cortical projection neurons is controlled by a Bcl11a/Bcl6‐dependent pathway

“…Several lines of evidence argue against this assumption. (i) extensive phenotype analyses of Nr2f1 mutants from various laboratories have implicated this factor in control of cortical progenitor proliferation as well as cortical patterning, and laminar fate determination in postmitotic neurons (Tocco et al , 2021 ). Yet, a direct role for Nr2f1 in control of postmitotic neuron survival has not been reported.…”

POSTRE: a tool to predict the pathological effects of human structural variants

“…In this case, POSTRE predicted a coding LOF mechanism, as the deletion eliminates one of the NR2F1 alleles. Both MEF2C and NR2F1 have been previously associated with neurodevelopmental deffects (Tocco et al, 2021; Zhang and Zhao, 2022). Therefore, the deletion could cause the loss of both NR2F1 and MEF2C function through distinct mechanisms, which in turn might define the phenotypic spectrum of this patient.…”

Nr2f1 controls mitochondrial dynamics in mouse adult-born hippocampal neurons

“…Notably, Nr2f1 binds to a promoter region closed to the transcription starting site (TSS) of the Mfn2 gene, which is associated to the H3K4me3 in the adult neural tissue ( Figure 4a ). We next crossed our Chip-seq dataset with previously published transcriptome data on the hippocampi of adult Nr2f1-heterozygous mice ( Nr2f1-het) (Chen et al , 2020), a validated BBSOAS mouse model (Bertacchi et al , 2019a; Jurkute et al , 2021; Tocco et al , 2021). By Gene Set Enrichment Analysis (GSEA), we found that among the 1053 enriched genes approximately 8% (82/1053) code for mitochondrial proteins, including the Mfn2 gene ( Figure 4b ).…”