Specification of cortical projection neurons

Ozkan, Abdulkadir; MacDonald, Jessica L.; Fame, Ryann M.; Itoh, Yoshio; Peter, Manuel; Durak, Omer; Macklis, Jeffrey D.

doi:10.1016/b978-0-12-814405-3.00019-9

Cited by 6 publications

(5 citation statements)

References 263 publications

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“…Molecular controls have been elucidated that govern the specification and differentiation of broad, hodologically distinct subtypes of neocortical projection neurons— CSN/subcerebral projection neurons (SCPN; CSN are a subset of SCPN), corticothalamic projection neurons (CThPN), and intracortical callosal projection neurons (CPN) (reviewed in (Greig et al, 2013; Ozkan et al, 2020)). CSN differentiation reflects a coordination of developmental programs that operate along temporal, subtype, and areal axes (Greig et al ., 2013), and these molecular controls together specify and differentiate CSN from other hodologically distinct projection neuron subtypes within the neocortex (Greig et al ., 2013; Ozkan et al ., 2020). CSN differentiation is also coordinated via interplay between CSN and other cell types (Thion et al, 2018; Ueno et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Lumican regulates cervical corticospinal axon collateralization via non-autonomous crosstalk between distinct corticospinal neuron subpopulations

Itoh

Sahni

et al. 2021

Preprint

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Corticospinal neurons (CSN) are the cortical projection neurons that innervate the spinal cord and some brainstem targets with segmental precision to control voluntary movement of specific functional motor groups, limb sections, or individual digits. CSN subpopulations exhibit striking axon targeting specificity from development into maturity: Evolutionarily newer rostrolateral CSN exclusively innervate bulbar-cervical targets (CSNBC-lat), while evolutionarily older caudomedial CSN (CSNmedial) are more heterogeneous, with distinct subpopulations extending axons to either bulbar-cervical or thoraco-lumbar segments. However, molecular regulation over specificity of CSN segmental target innervation is essentially unknown. The cervical cord, with its evolutionarily enhanced precision of forelimb movement, is innervated by multiple CSN subpopulations, suggesting inter-neuronal interactions in establishing cervical corticospinal circuitry. Here, we identify that Lumican, previously unrecognized in axon development, controls the balance of innervation between CSNBC-lat and CSNmedial within the cervical spinal cord. Remarkably, Lumican, an extracellular matrix protein expressed by CSNBC-lat, non-cell-autonomously suppresses axon collateralization in the cervical cord by CSNmedial. Intersectional viral labeling and mouse genetics further identify that Lumican controls axon collateralization by multiple CSN subpopulations in caudomedial sensorimotor cortex. These results identify inter-axonal molecular crosstalk between CSN subpopulations as a novel mechanism controlling corticospinal circuitry, target density, and competitive specificity. Further, this mechanism has potential implications for evolutionary diversification of corticospinal circuitry with finer scale precision.

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Section: Introductionmentioning

confidence: 99%

Lumican regulates cervical corticospinal axon collateralization via non-autonomous crosstalk between distinct corticospinal neuron subpopulations

Itoh

Sahni

et al. 2021

Preprint

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“…More broadly, differential expression of key controls in terms of both their levels and timing of expression, in addition to combinatorial co-expression with other key regulators, delineates differentiation of cortical projection neurons into progressively distinct subtypes with distinct targets and functional circuitry 2,49,[56][57][58][111][112][113] . For example, Fezf2 and Ctip2 are expressed more highly by SCPN/CSN relative to CThPN, but both subtypes are severely affected by loss of Fezf2 function 85,114 .…”

Section: In Contrast To Neurog2-only Activation Nvof-directed Neurons...mentioning

confidence: 99%

“…), so new neurons can form circuit-appropriate input and output connectivity 46 . Work from our lab and others have advanced this goal by identifying central molecular programs that first broadly, then increasingly precisely, control and regulate specification, diversity, and connectivity of specific cortical projection neuron subtypes during the period of their differentiation 2,[7][8][9][47][48][49][50][51][52][53][54][55][56][57][58][59] . According to an emerging model, complementary and exclusionary sets of proneural and class-, type-, and subtypespecific transcriptional controls act in a subtype-, stage-, and dose-dependent manner to direct distinct projection neuron differentiation trajectories, while repressing alternative fates 49 .…”

Section: Introductionmentioning

confidence: 99%

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors

Ozkan,

Padmanabhan,

Shipman

et al. 2024

Preprint

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Corticospinal neurons (CSN) centrally degenerate in amyotrophic lateral sclerosis (ALS), along with spinal motor neurons, and loss of voluntary motor function in spinal cord injury (SCI) results from damage to CSN axons. For functional regeneration of specifically affected neuronal circuitry in vivo, or for optimally informative disease modeling and/or therapeutic screening in vitro, it is important to reproduce the type or subtype of neurons involved. No such appropriate in vitro models exist with which to investigate CSN selective vulnerability and degeneration in ALS, or to investigate routes to regeneration of CSN circuitry for ALS or SCI, critically limiting the relevance of much research. Here, we identify that the HMG-domain transcription factor Sox6 is expressed by a subset of NG2+ endogenous cortical progenitors in postnatal and adult cortex, and that Sox6 suppresses a latent neurogenic program by repressing inappropriate proneural Neurog2 expression by progenitors. We FACS-purify these genetically accessible progenitors from postnatal mouse cortex and establish a pure culture system to investigate their potential for directed differentiation into CSN. We then employ a multi-component construct with complementary and differentiation-sharpening transcriptional controls (activating Neurog2, Fezf2, while antagonizing Olig2 with VP16:Olig2). We generate corticospinal-like neurons from SOX6+/NG2+ cortical progenitors, and find that these neurons differentiate with remarkable fidelity compared with corticospinal neurons in vivo. They possess appropriate morphological, molecular, transcriptomic, and electrophysiological characteristics, without characteristics of the alternate intracortical or other neuronal subtypes. We identify that these critical specifics of differentiation are not reproduced by commonly employed Neurog2-driven differentiation. Neurons induced by Neurog2 instead exhibit aberrant multi-axon morphology and express molecular hallmarks of alternate cortical projection subtypes, often in mixed form. Together, this developmentally-based directed differentiation from genetically accessible cortical progenitors sets a precedent and foundation for in vitro mechanistic and therapeutic disease modeling, and toward regenerative neuronal repopulation and circuit repair.

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“…Understanding of human-specific versions and subtleties of these networks and dynamics with hPSCs is very limited compared with major fundamental understanding of parallel neuron subtype differentiation in mice that has been deeply investigated over the past two decades. 6 , 7 , 8 , 9 …”

Section: Introductionmentioning

confidence: 99%

Limitations of fluorescent timer protein maturation kinetics to isolate transcriptionally synchronized human neural progenitor cells

Peter,

Shipman,

Heo

et al. 2024

iScience

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Specification of cortical projection neurons

Cited by 6 publications

References 263 publications

Lumican regulates cervical corticospinal axon collateralization via non-autonomous crosstalk between distinct corticospinal neuron subpopulations

Lumican regulates cervical corticospinal axon collateralization via non-autonomous crosstalk between distinct corticospinal neuron subpopulations

Directed differentiation of functional corticospinal-like neurons from endogenous SOX6+/NG2+ cortical progenitors

Limitations of fluorescent timer protein maturation kinetics to isolate transcriptionally synchronized human neural progenitor cells

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