Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders

Wagner, Nikolaus R.; MacDonald, Jessica L.

doi:10.1016/j.neuroscience.2020.12.009

Cited by 9 publications

(9 citation statements)

References 99 publications

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“…The pattern of immunostaining observed was similar to published CTIP2 immunostaining in the cortex (De León et al, 2019;Galazo et al, 2016;Ratie et al, 2020;Wagner et al, 2021) and similar to the expression pattern of Ctip2 mRNA detected with a riboprobe against Ctip2 mRNA by in-situ hybridization (Arlotta et al, 2005).…”

Section: Antibody Characterizationsupporting

confidence: 83%

Characterization and manipulation of Corticothalamic neurons in associative cortices using Syt6‐Cre transgenic mice

Vaasjo

Han

Thurmon

et al. 2021

J of Comparative Neurology

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Corticothalamic interactions between associative cortices and higher order thalamic nuclei are involved in high‐cognitive functions such as decision‐making and working memory. Corticothalamic neurons (CTn) in the prefrontal cortex and other associative areas have been much less studied than their counterparts in the primary sensory areas. The availability of characterized transgenic tools to study CTn in associative areas will facilitate their study and contribute to overcome the scarcity of data about their properties, network dynamics, and contribution to cognitive functions. Here, we characterized the Syt6‐Cre (KI148Gsat/Mmud) transgenic mouse line, by tracking expression of a Cre‐mediated reporter. In this line, Cre‐reporter is strongly expressed in the prefrontal, motor, cingulate, and retrosplenial cortices, as well as in other brain areas including the cerebellum and the olfactory tubercle. Cortical expression starts embryonically and reaches the adult expression pattern by postnatal day 15. In the cortex, Cre‐reporter is expressed by layer 6‐CTn and by layer 5‐CTn to a lesser extent. We quantified Syt6‐Cre+ CTn axon varicosities to estimate the distribution and density of putative corticothalamic driver and modulator inputs to thalamic nuclei in the medial, midline, intralaminar, anterior, and motor groups. Also, we characterized the effect of optogenetic stimulation of Syt6‐Cre+ neurons in the activity of the prefrontal cortex. CTn stimulation in the prefrontal cortex induces an oscillatory activity in the local field potential that resembles the cortical downstates typically observed during slow‐wave sleep or quiet wake.

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Section: Antibody Characterizationsupporting

confidence: 83%

Characterization and manipulation of Corticothalamic neurons in associative cortices using Syt6‐Cre transgenic mice

Vaasjo

Han

Thurmon

et al. 2021

J of Comparative Neurology

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“…It is thus conceivable that FGF signaling and Nr2f1 might act together as upstream regulators of a cascade of molecular events governing area patterning, whereas other genes such as Pax6 and Emx2 would act either as secondary downstream effectors or in parallel pathways and have a weaker effect on arealization. Finally, several chromatin regulators, such as the methyl-transferase Setd2 (Xu et al, 2021 ), the transcription co-regulator Cited2 (Fame et al, 2016 ; Wagner and MacDonald, 2021 ) and the epigenetic co-factor LIM Domain Only-4 ( Lmo4 ; Harb et al, 2016 ), have been reported to influence area identity refinement. Considering Nr2f1 ability to recruit epigenetic factors (Montemayor et al, 2010 ), it might be interesting to investigate whether these or similar chromatin regulators act in association with or under the control of Nr2f1 in the late arealization process.…”

Section: Nr2f1 Specifies the Identity Of Posterior Sensory Areasmentioning

confidence: 99%

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

Tocco

Bertacchi

Studer

2021

Front. Mol. Neurosci.

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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.

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“…Emx1-Cre mice ( Gorski et al, 2002 ) were obtained from The Jackson Laboratory ( RRID:IMSR_JAX:005628 ). Breeding was performed as described previously ( Wagner and MacDonald, 2021 ). Genotypes were assessed by PCR using the following primers: Cited2 flox/flox, flox/wt, and wt/wt were determined using – Cited2 Forward 5′-GTCTCAGCGTCTGCTCGTTT-3′; Cited2 Reverse 5′-CTGCTGCTGTTGGTGATGAT-3′.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Our previous work demonstrated that CITED2 is necessary for the expansion of intermediate progenitor cells (IPCs) in the SVZ, and the resulting generation of superficial layer callosal projection neurons ( Fame et al, 2016 ). Further, forebrain-specific Cited2 conditional knockout (cKO) leads to behavioral deficits associated with human neurodevelopmental disorders ( Wagner and MacDonald, 2021 ), highlighting the importance of CITED2 in cognitive function. Here, we investigate whether CITED2 is also necessary for the establishment of layer V callosal projection neurons, and whether it is repressed by members of the evolutionarily acquired Mirg /12qF1 miRNA cluster to refine the identity of layer V corticospinal projection neurons.…”

Section: Introductionmentioning

confidence: 99%

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miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity

Wagner

Sinha²,

Siththanandan³

et al. 2022

Front. Neurosci.

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The evolutionary emergence of the corticospinal tract and corpus callosum are thought to underpin the expansion of complex motor and cognitive abilities in mammals. Molecular mechanisms regulating development of the neurons whose axons comprise these tracts, the corticospinal and callosal projection neurons, remain incompletely understood. Our previous work identified a genomic cluster of microRNAs (miRNAs), Mirg/12qF1, that is unique to placental mammals and specifically expressed by corticospinal neurons, and excluded from callosal projection neurons, during development. We found that one of these, miR-409-3p, can convert layer V callosal into corticospinal projection neurons, acting in part through repression of the transcriptional regulator Lmo4. Here we show that miR-409-3p also directly represses the transcriptional co-regulator Cited2, which is highly expressed by callosal projection neurons from the earliest stages of neurogenesis. Cited2 is highly expressed by intermediate progenitor cells (IPCs) in the embryonic neocortex while Mirg, which encodes miR-409-3p, is excluded from these progenitors. miR-409-3p gain-of-function (GOF) in IPCs results in a phenocopy of established Cited2 loss-of-function (LOF). At later developmental stages, both miR-409-3p GOF and Cited2 LOF promote the expression of corticospinal at the expense of callosal projection neuron markers in layer V. Taken together, this work identifies previously undescribed roles for miR-409-3p in controlling IPC numbers and for Cited2 in controlling callosal fate. Thus, miR-409-3p, possibly in cooperation with other Mirg/12qF1 miRNAs, represses Cited2 as part of the multifaceted regulation of the refinement of neuronal cell fate within layer V, combining molecular regulation at multiple levels in both progenitors and post-mitotic neurons.

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Atypical Neocortical Development in the Cited2 Conditional Knockout Leads to Behavioral Deficits Associated with Neurodevelopmental Disorders

Cited by 9 publications

References 99 publications

Characterization and manipulation of Corticothalamic neurons in associative cortices using Syt6‐Cre transgenic mice

Characterization and manipulation of Corticothalamic neurons in associative cortices using Syt6‐Cre transgenic mice

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

miR-409-3p represses Cited2 to refine neocortical layer V projection neuron identity

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