An early cortical progenitor-specific mechanism regulates thalamocortical innervation
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE159006 | GEO | 2023/09/25
REPOSITORIES: GEO
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Project description:The cortical subplate is critical in regulating the entry of thalamocortical sensory afferents into the cortex. These afferents reach the subplate at embryonic day (E)15.5 in the mouse, but "wait" for several days, entering the cortical plate postnatally. We report that when transcription factor LHX2 is lost in E11.5 cortical progenitors, which give rise to subplate neurons, thalamocortical afferents display premature, exuberant ingrowth into the E15.5 cortex. Embryonic mutant subplate neurons are correctly positioned below the cortical plate, but they display an altered transcriptome and immature electrophysiological properties during the waiting period. The sensory thalamus in these cortex-specific Lhx2 mutants displays atrophy and by postnatal day (P) 7, sensory innervation to the cortex is nearly eliminated leading to a loss of the somatosensory barrels. Strikingly, these phenotypes do not manifest if LHX2 is lost in postmitotic subplate neurons, and the transcriptomic dysregulation in the subplate resulting from postmitotic loss of LHX2 is vastly distinct from that seen when LHX2 is lost in progenitors. These results demonstrate a mechanism operating in subplate progenitors that has profound consequences on the growth of thalamocortical axons into the cortex.SIGNIFICANCE STATEMENT Thalamocortical nerves carry sensory information from the periphery to the cortex. When they first grow into the embryonic cortex, they "wait" at the subplate, a structure critical for the guidance and eventual connectivity of thalamic axons with their cortical targets. How the properties of subplate neurons are regulated is unclear. We report that transcription factor LHX2 is required in the progenitor "mother" cells of the cortical primordium when they are producing their "daughter" subplate neurons, in order for the thalamocortical pathway to wait at the subplate. Without LHX2 function in subplate progenitors, thalamocortical axons grow past the subplate, entering the cortical plate prematurely. This is followed by their eventual attrition and, consequently, a profound loss of sensory innervation of the mature cortex.
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Project description:An early cortical progenitor-specific mechanism regulates thalamocortical innervation
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Project description:Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons. Subplate neurons (SPNs), strategically positioned at the interface of cortical grey and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pan-cortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating non-cell autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate-thalamocortical axon co-fasciculation (“handshake”), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate-thalamocortical axon co-fasciculation and extracellular matrix assembly. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.
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Project description:Radial glial progenitor cells (RGPs) are the major neural progenitor cells that generate neurons and glia in the developing mammalian cerebral cortex1-4. In RGPs, the centrosome is positioned away from the nucleus at the apical surface of the ventricular zone of the cerebral cortex5-8. However, the molecular basis and precise function of this distinctive subcellular organization of the centrosome are largely unknown. Here we show in mice that anchoring of the centrosome to the apical membrane controls the mechanical properties of cortical RGPs, and consequently their mitotic behaviour and the size and formation of the cortex. The mother centriole in RGPs develops distal appendages that anchor it to the apical membrane. Selective removal of centrosomal protein 83 (CEP83) eliminates these distal appendages and disrupts the anchorage of the centrosome to the apical membrane, resulting in the disorganization of microtubules and stretching and stiffening of the apical membrane. The elimination of CEP83 also activates the mechanically sensitive yes-associated protein (YAP) and promotes the excessive proliferation of RGPs, together with a subsequent overproduction of intermediate progenitor cells, which leads to the formation of an enlarged cortex with abnormal folding. Simultaneous elimination of YAP suppresses the cortical enlargement and folding that is induced by the removal of CEP83. Together, these results indicate a previously unknown role of the centrosome in regulating the mechanical features of neural progenitor cells and the size and configuration of the mammalian cerebral cortex.
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Project description:Orderly division of radial glial progenitors (RGPs) in the developing mammalian cerebral cortex generates deep and superficial layer neurons progressively. However, the mechanisms that control RGP behavior and precise neuronal output remain elusive. Here, we show that the oxidative stress level progressively increases in the developing mouse cortex and regulates RGP behavior and neurogenesis. As development proceeds, numerous gene pathways linked to reactive oxygen species (ROS) and oxidative stress exhibit drastic changes in RGPs. Selective removal of PRDM16, a transcriptional regulator highly expressed in RGPs, elevates ROS level and induces expression of oxidative stress-responsive genes. Coinciding with an enhanced level of oxidative stress, RGP behavior was altered, leading to abnormal deep and superficial layer neuron generation. Simultaneous expression of mitochondrially targeted catalase to reduce cellular ROS levels significantly suppresses cortical defects caused by PRDM16 removal. Together, these findings suggest that oxidative stress actively regulates RGP behavior to ensure proper neurogenesis in the mammalian cortex.
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Project description:Mammalian brains are highly conserved at both the neuroanatomical and gene expression levels. However, the subplate is a neocortical subregion distinguished by a markedly different developmental trajectory among primates compared to other mammals. Moreover, the molecular mechanisms driving these species differences in subplate development remain mostly unknown. Here, we show that human FOXP2, a transcription factor important for speech and language, regulates gene expression programs consistent with subplate neuron expression patterns. These transcriptional profiles have unique overlaps with in vivo data from human fetal brain. We also distinguish DNA-dependent and DNA-independent mechanisms for human FOXP2 to repress patterns of germinal zone expression and promote excitatory neuron gene expression patterns.
2019-05-07 | GSE111353 | GEO
Project description:Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity
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Project description:Thalamic inputs strongly drive neurons in the primary visual cortex, even though these neurons constitute only approximately 5% of the synapses on layer 4 spiny stellate simple cells. We modeled the feedforward excitatory and inhibitory inputs to these cells based on in vivo recordings in cats, and we found that the reliability of spike transmission increased steeply between 20 and 40 synchronous thalamic inputs in a time window of 5 milliseconds, when the reliability per spike was most energetically efficient. The optimal range of synchronous inputs was influenced by the balance of background excitation and inhibition in the cortex, which could gate the flow of information into the cortex. Ensuring reliable transmission by spike synchrony in small populations of neurons may be a general principle of cortical function.
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Project description:Anatomical studies have led to the assertion that intratelencephalic and pyramidal tract cortical neurons innervate different striatal projection neurons. To test this hypothesis, we measured the responses of mouse striatal neurons to optogenetic activation of intratelencephalic and pyramidal tract axons. Contrary to expectation, direct and indirect pathway striatal spiny projection neurons responded to both intratelencephalic and pyramidal tract activation, arguing that these cortical networks innervate both striatal projection neurons.
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Project description:Although high amounts of reactive oxygen species (ROS) can damage cells, ROS can also play roles as second messengers, regulating diverse cellular processes. Here, we report that embryonic mouse cerebral cortical neural progenitor cells (NPCs) exhibit intermittent spontaneous bursts of mitochondrial superoxide (SO) generation (mitochondrial SO flashes) that require transient opening of membrane permeability transition pores (mPTP). This quantal SO production negatively regulates NPC self-renewal. Mitochondrial SO scavengers and mPTP inhibitors reduce SO flash frequency and enhance NPC proliferation, whereas prolonged mPTP opening and SO generation increase SO flash incidence and decrease NPC proliferation. The inhibition of NPC proliferation by mitochondrial SO involves suppression of extracellular signal-regulated kinases. Moreover, mice lacking SOD2 (SOD2-/- mice) exhibit significantly fewer proliferative NPCs and differentiated neurons in the embryonic cerebral cortex at midgestation compared with wild-type littermates. Cultured SOD2-/- NPCs exhibit a significant increase in SO flash frequency and reduced NPC proliferation. Taken together, our findings suggest that mitochondrial SO flashes negatively regulate NPC self-renewal in the developing cerebral cortex.
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