•COUP-TFI transcriptional action depends on cellular context and co-factor accessibility.•COUP‐TFI imparts sensory identity during neocortical area map formation.•Temporal competence in neural ...progenitors depends on COUP-TF expression levels.•COUP‐TFI-mediated control of cortical development impacts on complex animal behaviors.•NR2F1 haploinsufficiency leads to syndromic visual and cognitive deficits in humans.
Transcription factors are expressed in a dynamic fashion both in time and space during brain development, and exert their roles by activating a cascade of multiple target genes. This implies that understanding the precise function of a transcription factor becomes a challenging task. In this review, we will focus on COUP-TFI (or NR2F1), a nuclear receptor belonging to the superfamily of the steroid/thyroid hormone receptors, and considered to be one of the major transcriptional regulators orchestrating cortical arealization, cell-type specification and maturation. Recent data have unraveled the multi-faceted functions of COUP-TFI in the development of several mouse brain structures, including the neocortex, hippocampus and ganglionic eminences. Despite NR2F1 mutations and deletions in humans have been linked to a complex neurodevelopmental disease mainly associated to optic atrophy and intellectual disability, its role during the formation of the retina and optic nerve remains unclear. In light of its major influence in cortical development, we predict that its haploinsufficiency might be the cause of other cognitive diseases, not identified so far. Mouse models offer a unique opportunity of dissecting COUP-TFI function in different regions during brain assembly; hence, the importance of comparing and discussing common points linking mouse models to human patients’ symptoms.
The subdivision of the mammalian neocortex into specialized modality-specific areas is responsible for the processing of sensory information followed by an adequate motor response. This process, ...called arealization, depends on the graded expression of transcription factors in neocortical progenitors and postmitotic neurons prenatally, and on external activity-dependent cues driven by thalamocortical axons during postnatal stages. Thalamic inputs are guided within an intrinsically determined genetic framework to selectively target and innervate layer 4 (L4) cortical neurons in a somatotopic manner. L4 spiny stellate neurons are excitatory locally projecting neurons, which undergo a drastic dendrite remodeling during the first postnatal week and represent the principal sensory gateway to the neocortex. In this review, we will discuss the way intrinsic cortical gene regulation and extrinsic activity-dependent inputs instruct the cellular reorganization of L4 spiny stellate neurons, necessary for proper formation of the barrel cortex during the development of primary somatosensory maps.
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
haploinsufficiency. The
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.
GABAergic interneurons are highly heterogeneous and originate in the subpallium mainly from the medial (MGE) and caudal (CGE) ganglionic eminences according to a precise temporal sequence. ...MGE-derived cells disperse dorsally and migrate towards all regions of the cortex, but little is known about how CGE-derived cells reach their targets during development. Here, we unravel the existence of two novel CGE caudo-rostral migratory streams, one located laterally (LMS) and the other one more medially (MMS), that, together with the well-known caudal migratory stream (CMS), contribute to populate the neocortex, hippocampus and amygdala. These paths appear in a precise temporal sequence and express a distinct combination of transcription factors, such as SP8, PROX1, COUP-TFI and COUP-TFII. By inactivating COUP-TFI in developing interneurons, the lateral and medial streams are perturbed and expression of SP8 and COUP-TFII affected. As a consequence, adult mutant neocortices have laminar-specific alterations of distinct cortical interneuron subtypes. Overall, we propose that the existence of spatially and temporally regulated migratory paths in the subpallium contributes to the laminar distribution and specification of distinct interneuron subpopulations in the adult brain.
Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here, we show in mouse ...that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of Krox20-expressing neural crest cells shows a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of
function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest
-deficient embryos. Genetic lineage tracing in
mutant mice shows that endothelial-derived cells are normal, whereas neural crest-derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of
-expressing cells is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings demonstrate a crucial role for
in arterial valve development and reveal that an excess of neural crest cells may be associated with bicuspid aortic valve.
Axonal projections from layer V neurons of distinct neocortical areas are topographically organized into discrete clusters within the pontine nuclei during the establishment of voluntary movements. ...However, the molecular determinants controlling corticopontine connectivity are insufficiently understood. Here, we show that an intrinsic cortical genetic program driven by Nr2f1 graded expression is directly implicated in the organization of corticopontine topographic mapping. Transgenic mice lacking cortical expression of Nr2f1 and exhibiting areal organization defects were used as model systems to investigate the arrangement of corticopontine projections. By combining three-dimensional digital brain atlas tools, Cre-dependent mouse lines and axonal tracing, we show that Nr2f1 expression in postmitotic neurons spatially and temporally controls somatosensory topographic projections, whereas expression in progenitor cells influences the ratio between corticopontine and corticospinal fibres passing the pontine nuclei. We conclude that cortical gradients of area-patterning genes are directly implicated in the establishment of a topographic somatotopic mapping from the cortex onto pontine nuclei.
Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the ...importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.
•Mitochondrial dysfunction in the pathogenesis of neurodevelopmental disorders.•The pleiotropic function of mitochondria in adult neurogenesis and brain plasticity.•Adult neurogenesis as a model to study the role of mitochondria in neurodevelopmental disorders.•NR2F1 regulates mitochondria in adult hippocampal neurogenesis.•Involvement of brain mitochondrial dysfunction in BBSOAS.
Deciphering the structural effects of gene variants is essential for understanding the pathophysiological mechanisms of genetic diseases. Using a neurodevelopmental disorder called ...Bosch‐Boonstra‐Schaaf Optic Atrophy Syndrome (BBSOAS) as a genetic disease model, we applied structural bioinformatics and Genetic Code Expansion (GCE) strategies to assess the pathogenic impact of human NR2F1 variants and their binding with known and novel partners. While the computational analyses of the NR2F1 structure delineated the molecular basis of the impact of several variants on the isolated and complexed structures, the GCE enabled covalent and site‐specific capture of transient supramolecular interactions in living cells. This revealed the variable quaternary conformations of NR2F1 variants and highlighted the disrupted interplay with dimeric partners and the newly identified co‐factor, CRABP2. The disclosed consequence of the pathogenic mutations on the conformation, supramolecular interplay, and alterations in the cell cycle, viability, and sub‐cellular localization of the different variants reflect the heterogeneous disease spectrum of BBSOAS and set up novel foundation for unveiling the complexity of neurodevelopmental diseases.
Autosomal recessive mutation of HOXB1 and Hoxb1 causes sensorineural hearing loss in patients and mice, respectively, characterized by the presence of higher auditory thresholds; however, the origin ...of the defects along the auditory pathway is still unknown. In this study, we assessed whether the abnormal auditory threshold and malformation of the sensory auditory cells, the outer hair cells, described in Hoxb1null mutants depend on the absence of efferent motor innervation, or alternatively, is due to altered sensory auditory components. By using a whole series of conditional mutant mice, which inactivate Hoxb1 in either rhombomere 4-derived sensory cochlear neurons or efferent motor neurons, we found that the hearing phenotype is mainly reproduced when efferent motor neurons are specifically affected. Our data strongly suggest that the interactions between olivocochlear motor neurons and outer hair cells during a critical postnatal period are crucial for both hair cell survival and the establishment of the cochlear amplification of sound.
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