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

Chiara Tocco,Michèle Studer,Michele Bertacchi

doi:10.3389/fnmol.2021.767965

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.

Highlights

Neurodevelopmental disorders (NDDs) are a highly heterogeneous class of mainly genetic pathological conditions, often due to defects of early mechanisms of brain development, such as cell proliferation, migration and differentiation, as well as activity and connectivity
The high heterogeneity of NDDs is reported at both genetic and clinical levels, with several causative genes and variable genotype-dependent severity of multiple clinical signs (Cristino et al, 2014; Hormozdiari et al, 2015; Parenti et al, 2020). Despite such heterogeneity, NDD patients carrying distinct mutations often present a comorbidity of multiple symptoms [e.g., intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy; van Bokhoven, 2011; Du et al, 2018; Parenti et al, 2020], suggesting the existence of common molecular pathways converging on similar clinical features
From the peripheral-most relay points of the visual system, i.e., the retina and the optic nerve, to more central brain structures deputed to the analysis of visual stimuli, such as the visual thalamus and cortices, we summarize how Nr2f1/NR2F1 graded expression in distinct relay-points of the developing visual system impacts the function of mouse and human vision (Figure 7A)

Summary

INTRODUCTION

Neurodevelopmental disorders (NDDs) are a highly heterogeneous class of mainly genetic pathological conditions, often due to defects of early mechanisms of brain development, such as cell proliferation, migration and differentiation, as well as activity and connectivity. Nr2f1 can either positively or negatively regulate cell proliferation, differentiation, and migration, depending on the developmental time or co-expression of key co-factors Despite this high level of complexity, several studies have started to unravel Nr2f1 complex functions, especially in the context of neural progenitors and their progeny. Their main effectors are area patterning genes such as Pax, Sp8, and Emx among others, and Nr2f1 itself (Grove and FukuchiShimogori, 2003; O’Leary and Sahara, 2008; Alfano and Studer, 2013; Figure 3B-generation of genetic coordinates) Their combinatorial expression in neocortical progenitors provides precise spatial coordinates and regulates cell differentiation, area identity, neuronal maturation and network connectivity and function. The visual impairments at the cortical level due to reduced Nr2f1 dosage could contribute to one of the main features of ID reported in BBSOAS children

CONCLUSIONS AND FUTURE DIRECTIONS

Mouse model

Findings

Neocortex Connectivity