scholarly journals A microRNA cluster downstream of the selector gene Fezf2 coordinates fate specification with dendritic branching in cortical neurons

2021 ◽  
Author(s):  
Asha Iyer ◽  
Verl B Siththanandan ◽  
Victoria Lu ◽  
Ramesh V Nair ◽  
Lee O Vaasjo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cortical Neurons ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Dendritic Branching ◽  
Microrna Cluster ◽  
The Central Nervous System ◽  
Callosal Projection ◽  
Cortical Projection Neuron

In the cerebral cortex, cortical projection neurons comprise classes of neurons project to distant regions of the central nervous system. These neurons develop from the same progenitor pool, but they acquire strikingly different inputs and outputs to underpin strikingly different functions. The question of how corticospinal projection neurons - involved in motor function and implicated in paralysis - and callosal projection neurons - involved in cognitive function and implicated in autism - develop represents a fundamental and clinically important question in neurodevelopment. A network of transcription factors, including the selector gene Fezf2, is central to specifying cortical projection neuron fates. Gene regulation up- and down-stream of these transcription factors, however, is not well understood, particularly as it relates to the development of the major inputs to cortical projection neurons. Here we show that the miR-193b~365 microRNA cluster downstream of Fezf2 cooperatively represses the signaling molecule Mapk8, and impacts dendritic branching of cortical projection neurons.

scholarly journals An evolutionarily acquired microRNA shapes development of mammalian cortical projections

2020 ◽  
Author(s):  
Jessica L Diaz ◽  
Verl B Siththanandan ◽  
Victoria Lu ◽  
Nicole Gonzalez-Nava ◽  
Lincoln Pasquina ◽  
...  
Keyword(s):  
Corpus Callosum ◽  
Cognitive Skills ◽  
Corticospinal Tract ◽  
Projection Neuron ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Complex Motor ◽  
Callosal Projection ◽  
Cortical Projection Neuron

AbstractThe corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are co-expressed across multiple projection neuron subtypes. Here, we discover seventeen CSMN-enriched microRNAs (miRNAs), fifteen of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is the first demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians’ increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.Significance StatementThe mammalian central nervous system contains unique projections from the cerebral cortex thought to underpin complex motor and cognitive skills, including the corticospinal tract and corpus callosum. The neurons giving rise to these projections - corticospinal and callosal projection neurons - develop from the same progenitors, but acquire strikingly different fates. The broad evolutionary conservation of known genes controlling cortical projection neuron fates raises the question of how the more narrowly conserved corticospinal and callosal projections evolved. We identify a microRNA cluster selectively expressed by corticospinal projection neurons and exclusive to placental mammals. One of these microRNAs promotes corticospinal fate via regulation of the callosal gene LMO4, suggesting a mechanism whereby microRNA regulation during development promotes evolution of neuronal diversity.

scholarly journals Basic Helix-Loop-Helix Transcription Factors Cooperate To Specify a Cortical Projection Neuron Identity

2007 ◽  
Vol 28 (5) ◽  
pp. 1456-1469 ◽  
Author(s):  
Pierre Mattar ◽  
Lisa Marie Langevin ◽  
Kathryn Markham ◽  
Natalia Klenin ◽  
Salma Shivji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Projection Neuron ◽  
Luciferase Assay ◽  
Bhlh Gene ◽  
Cortical Projection ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Bhlh Genes ◽  
Cortical Projection Neuron

ABSTRACT Several transcription factors are essential determinants of a cortical projection neuron identity, but their mode of action (instructive versus permissive) and downstream genetic cascades remain poorly defined. Here, we demonstrate that the proneural basic helix-loop-helix (bHLH) gene Ngn2 instructs a partial cortical identity when misexpressed in ventral telencephalic progenitors, inducing ectopic marker expression in a defined temporal sequence, including early (24 h; Nscl2), intermediate (48 h; BhlhB5), and late (72 h; NeuroD, NeuroD2, Math2, and Tbr1) target genes. Strikingly, cortical gene expression was much more rapidly induced by Ngn2 in the dorsal telencephalon (within 12 to 24 h). We identify the bHLH gene Math3 as a dorsally restricted Ngn2 transcriptional target and cofactor, which synergizes with Ngn2 to accelerate target gene transcription in the cortex. Using a novel in vivo luciferase assay, we show that Ngn2 generates only ∼60% of the transcriptional drive in ventral versus dorsal telencephalic domains, an activity that is augmented by Math3, providing a mechanistic basis for regional differences in Ngn2 function. Cortical bHLH genes thus cooperate to control transcriptional strength, thereby temporally coordinating downstream gene expression.

scholarly journals Directional Asymmetry of Neurons in Cortical Areas MT and MST Projecting to the NOT-DTN in Macaques

2002 ◽  
Vol 87 (4) ◽  
pp. 2113-2123 ◽  
Author(s):  
K.-P. Hoffmann ◽  
F. Bremmer ◽  
A. Thiele ◽  
C. Distler
Keyword(s):  
Cortical Neurons ◽  
Optic Tract ◽  
Directional Asymmetry ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Directional Bias ◽  
Stimulus Movement ◽  
Equal Distribution ◽  
Temporal Area ◽  
Optokinetic Reflex

The cortical projection to the subcortical pathway underlying the optokinetic reflex was studied using antidromic electrical stimulation in the midbrain structures nucleus of the optic tract and dorsal terminal nucleus of the accessory optic system (NOT-DTN) while simultaneously recording from cortical neurons in the superior temporal sulcus (STS) of macaque monkeys. Projection neurons were found in all subregions of the middle temporal area (MT) as well as in the medial superior temporal area (MST). Antidromic latencies ranged from 0.9 to 6 ms with a median of 1.8 ms. There was a strong bias in the population of cortical neurons projecting to the NOT-DTN for ipsiversive stimulus movement (towards the recording side), whereas in the population of cortical neurons not projecting to the NOT-DTN a more or less equal distribution of stimulus directions was evident. Our data indicate that there is no special area in the posterior STS coding for ipsiversive horizontal stimulus movement. Instead, a specific selection of cortical neurons from areas MT and MST forms the projection to the NOT-DTN and as a subpopulation has the same directional bias as their subcortical target neurons. These findings are discussed in relation to the functional grouping of cortical output as an organizational principle for specific motor responses.

scholarly journals Increased Callosal Connectivity in Reeler Mice Revealed by Brain-Wide Input Mapping of VIP Neurons in Barrel Cortex

2020 ◽  
Author(s):  
Georg Hafner ◽  
Julien Guy ◽  
Mirko Witte ◽  
Pavel Truschow ◽  
Alina Rüppel ◽  
...  
Keyword(s):  
Long Range ◽  
Cortical Neurons ◽  
Barrel Cortex ◽  
Projection Neurons ◽  
Subcortical Structures ◽  
Virus Tracing ◽  
Cortical Inputs ◽  
Callosal Projection ◽  
To Receive ◽  
The Brain

Abstract The neocortex is composed of layers. Whether layers constitute an essential framework for the formation of functional circuits is not well understood. We investigated the brain-wide input connectivity of vasoactive intestinal polypeptide (VIP) expressing neurons in the reeler mouse. This mutant is characterized by a migration deficit of cortical neurons so that no layers are formed. Still, neurons retain their properties and reeler mice show little cognitive impairment. We focused on VIP neurons because they are known to receive strong long-range inputs and have a typical laminar bias toward upper layers. In reeler, these neurons are more dispersed across the cortex. We mapped the brain-wide inputs of VIP neurons in barrel cortex of wild-type and reeler mice with rabies virus tracing. Innervation by subcortical inputs was not altered in reeler, in contrast to the cortical circuitry. Numbers of long-range ipsilateral cortical inputs were reduced in reeler, while contralateral inputs were strongly increased. Reeler mice had more callosal projection neurons. Hence, the corpus callosum was larger in reeler as shown by structural imaging. We argue that, in the absence of cortical layers, circuits with subcortical structures are maintained but cortical neurons establish a different network that largely preserves cognitive functions.

scholarly journals Lmo4 and Clim1 Progressively Delineate Cortical Projection Neuron Subtypes during Development

2009 ◽  
Vol 19 (suppl_1) ◽  
pp. i62-i69 ◽  
Author(s):  
Eiman Azim ◽  
Sara J. Shnider ◽  
Gustav Y. Cederquist ◽  
U. Shivraj Sohur ◽  
Jeffrey D. Macklis
Keyword(s):  
Projection Neuron ◽  
Cortical Projection ◽  
Cortical Projection Neuron

scholarly journals Mechanisms underlying serotonergic excitation of callosal projection neurons

2017 ◽  
Author(s):  
Emily K. Stephens ◽  
Arielle L. Baker ◽  
Allan T. Gulledge
Keyword(s):  
Intracellular Calcium ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Projection Neurons ◽  
Calcium Dependent ◽  
M Current ◽  
Cation Conductance ◽  
Cortical Pyramidal Neurons ◽  
Excitatory Responses ◽  
Callosal Projection

AbstractSerotonin (5-HT) selectively excites subpopulations of pyramidal neurons in the neocortex via activation of 5-HT2A (2A) receptors coupled to Gq subtype G-protein alpha subunits. Gq-mediated excitatory responses have been attributed primarily to suppression of potassium conductances, including those mediated by KV7 potassium channels (i.e., the M-current), or activation of nonspecific cation conductances that underly calcium-dependent afterdepolarizations (ADPs). However, 2A-dependent excitation of cortical neurons has not been extensively studied, and no consensus exists regarding the underlying ionic effector(s) involved. We tested potential mechanisms of serotonergic excitation in commissural/callosal projection neurons (COM neurons) in layer 5 of the mouse medial prefrontal cortex, a subpopulation of cortical pyramidal neurons that exhibit 2A-dependent excitation in response to 5-HT. In baseline conditions, 5-HT enhanced the rate of action potential generation in COM neurons experiencing suprathreshold somatic current injection. This serotonergic excitation was occluded by activation of muscarinic acetylcholine (ACh) receptors, confirming that 5-HT acts via the same Gq-signaling cascades engaged by ACh. Like ACh, 5-HT promoted the generation of calcium-dependent ADPs following spike trains. However, calcium was not necessary for serotonergic excitation, as responses to 5-HT were enhanced (by >100%), rather than reduced, by chelation of intracellular calcium with 10 mM BAPTA. This suggests intracellular calcium negatively regulates additional ionic conductances contributing to 2A excitation. Removal of extracellular calcium had no effect when intracellular calcium signaling was intact, but suppressed 5-HT response amplitudes, by about 50% (i.e., back to normal baseline values) when BAPTA was included in patch pipettes. This suggests that 2A excitation involves activation of a nonspecific cation conductance that is both calcium-sensitive and calcium-permeable. M-current suppression was found to be a third ionic effector, as blockade of KV7 channels with XE991 (10 μM) reduced serotonergic excitation by ∼50% in control conditions, and by ∼30% with intracellular BAPTA present. These findings demonstrate a role for at least three distinct ionic effectors, including KV7 channels, a calcium-sensitive and calcium-permeable nonspecific cation conductance, and the calcium-dependent ADP conductance, in mediating serotonergic excitation of COM neurons.

scholarly journals Genome-wide target analysis of NEUROD2 provides new insights into regulation of cortical projection neuron migration and differentiation

BMC Genomics ◽  
2015 ◽  
Vol 16 (1) ◽  
Author(s):  
Efil Bayam ◽  
Gulcan Semra Sahin ◽  
Gizem Guzelsoy ◽  
Gokhan Guner ◽  
Alkan Kabakcioglu ◽  
...  
Keyword(s):  
Projection Neuron ◽  
Cortical Projection ◽  
Neuron Migration ◽  
Target Analysis ◽  
Genome Wide ◽  
Cortical Projection Neuron

scholarly journals Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons

2015 ◽  
Vol 112 (44) ◽  
pp. 13693-13698 ◽  
Author(s):  
Adán de Salas-Quiroga ◽  
Javier Díaz-Alonso ◽  
Daniel García-Rincón ◽  
Floortje Remmers ◽  
David Vega ◽  
...  
Keyword(s):  
Prenatal Exposure ◽  
Cortical Neurons ◽  
Time Window ◽  
Projection Neuron ◽  
Fine Motor ◽  
Adult Offspring ◽  
Neuron Development ◽  
Cortical Projection ◽  
Genetic Ablation ◽  
The Impact

The CB1 cannabinoid receptor, the main target of Δ9-tetrahydrocannabinol (THC), the most prominent psychoactive compound of marijuana, plays a crucial regulatory role in brain development as evidenced by the neurodevelopmental consequences of its manipulation in animal models. Likewise, recreational cannabis use during pregnancy affects brain structure and function of the progeny. However, the precise neurobiological substrates underlying the consequences of prenatal THC exposure remain unknown. As CB1 signaling is known to modulate long-range corticofugal connectivity, we analyzed the impact of THC exposure on cortical projection neuron development. THC administration to pregnant mice in a restricted time window interfered with subcerebral projection neuron generation, thereby altering corticospinal connectivity, and produced long-lasting alterations in the fine motor performance of the adult offspring. Consequences of THC exposure were reminiscent of those elicited by CB1 receptor genetic ablation, and CB1-null mice were resistant to THC-induced alterations. The identity of embryonic THC neuronal targets was determined by a Cre-mediated, lineage-specific, CB1 expression-rescue strategy in a CB1-null background. Early and selective CB1 reexpression in dorsal telencephalic glutamatergic neurons but not forebrain GABAergic neurons rescued the deficits in corticospinal motor neuron development of CB1-null mice and restored susceptibility to THC-induced motor alterations. In addition, THC administration induced an increase in seizure susceptibility that was mediated by its interference with CB1-dependent regulation of both glutamatergic and GABAergic neuron development. These findings demonstrate that prenatal exposure to THC has long-lasting deleterious consequences in the adult offspring solely mediated by its ability to disrupt the neurodevelopmental role of CB1 signaling.

scholarly journals Mutual regulation between Satb2 and Fezf2 promotes subcerebral projection neuron identity in the developing cerebral cortex

2015 ◽  
Vol 112 (37) ◽  
pp. 11702-11707 ◽  
Author(s):  
William L. McKenna ◽  
Christian F. Ortiz-Londono ◽  
Thomas K. Mathew ◽  
Kendy Hoang ◽  
Sol Katzman ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Projection Neuron ◽  
Dependent Manner ◽  
Neuron Development ◽  
Cortical Projection ◽  
Expression Of Genes ◽  
Axon Development ◽  
Mutual Regulation ◽  
A Cell ◽  
Cortical Projection Neuron

Generation of distinct cortical projection neuron subtypes during development relies in part on repression of alternative neuron identities. It was reported that the special AT-rich sequence-binding protein 2 (Satb2) is required for proper development of callosal neuron identity and represses expression of genes that are essential for subcerebral axon development. Surprisingly, Satb2 has recently been shown to be necessary for subcerebral axon development. Here, we unravel a previously unidentified mechanism underlying this paradox. We show that SATB2 directly activates transcription of forebrain embryonic zinc finger 2 (Fezf2) and SRY-box 5 (Sox5), genes essential for subcerebral neuron development. We find that the mutual regulation between Satb2 and Fezf2 enables Satb2 to promote subcerebral neuron identity in layer 5 neurons, and to repress subcerebral characters in callosal neurons. Thus, Satb2 promotes the development of callosal and subcerebral neurons in a cell context-dependent manner.

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