Instructing Perisomatic Inhibition by Direct Lineage Reprogramming of Neocortical Projection Neurons

Ye, Zhanlei; Mostajo-Radji, Mohammed A.; Brown, Juliana; Rouaux, Caroline; Tomassy, Giulio Srubek; Hensch, Takao K.; Arlotta, Paola

doi:10.1016/j.neuron.2015.10.006

Cited by 59 publications

(60 citation statements)

References 42 publications

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“…qPCR (data not shown) and RNAseq data ( Fig. 4e) confirmed that purified CSN expressed markers typical of the cortical layer V subcerebral projection neurons, and did not express any marker typical of upper layer projection neurons 20,24,25 , and vice-versa ( Fig. 4e).…”

Section: Purification Of Adult Csn Under Healthy and Neurodegenerativmentioning

confidence: 66%

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Marques

Fischer

Keime

et al. 2019

Preprint

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease clinically defined as the combined degeneration of corticospinal and corticobulbar neurons (CSN), and bulbar and spinal motor neurons (MN). A growing body of evidence points to the motor cortex, where CSN are located, as the potential initiation site of ALS. However, little is known about the spatiotemporal dynamics of CSN degeneration and the molecular pathways involved. Here, we show in the Sod1 G86R mouse model of ALS that CSN loss precedes MN degeneration and that CSN and MN degenerations are somatotopically related, highlighting the relevance of CSN to ALS onset and progression. To gain insights into the molecular mechanisms that selectively trigger CSN degeneration, we purified CSN from the motor and somatosensory cortex of adult mice and analysed their transcriptome from presymptomatic ages to disease end-stage. Significant RNA metabolism and splicing alterations, novel in the context of Sod1 mutation, were identified, including mis-splicing events that largely trigger genes involved in neuronal functions. Together, the data indicate that CSN dysfunction and degeneration upon mutant Sod1 expression involve alterations of RNA metabolism and splicing, emphasizing shared mechanisms across various ALS-related genes.3 ALS is an incurable and fatal neurodegenerative disease that mostly starts in adulthood with a rapidly progressing paralysis and death within only 2 to 5 years of diagnosis 1,2 . In clinics, ALS is defined as the combined degeneration of both corticospinal and corticobulbar neurons (CSN, or upper motor neurons) whose cell bodies are located in the cerebral cortex and that extend axons to the medulla and spinal cord, and of spinal and bulbar motor neurons (MN, or lower motor neurons) whose cell bodies are located in the medulla and spinal cord, and that connect to the skeletal muscles. If the cellular and molecular mechanisms behind MN degeneration are relatively well known, the numerous related clinical trials have unfortunately failed to translate into improved treatment of ALS 1-4 , a discrepancy that contributed to the emergence of the CSN and the overall cerebral cortex as alternative therapeutic targets.A growing body of evidence points to the motor cortex as the likely initiation site of ALS 5,6 . A first series of arguments arose from the recent genetic, pathological and clinical evolution links established between ALS and FrontoTemporal Dementia (FTD), a neurodegenerative disease that affects solely the cerebral cortex and results in behavioural and cognitive deficits 7 . A second series of arguments emerged following extensive examination of the TDP-43 aggregates, a pathological hallmark of the disease in post-mortem brains from ALS patients, identifying the motor cortex as the most affected region of the brain, and leading to the corticofugal hypothesis 8-10 which proposes a sequential pattern of pathology spreading from the motor cortex to its projection sites. Finally, transcranial magnetic stimulation studi...

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Section: Purification Of Adult Csn Under Healthy and Neurodegenerativmentioning

confidence: 66%

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Marques

Fischer

Keime

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

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“…The specialization of CPN subtypes is largely determined by their axonal outputs [30][31][32] . Thus, we asked if axonal targeting specificities of CPN subtypes were altered in absence of NeuroD2.…”

Section: Altered Relative Size Of Cortical Layers In Neurod2-deficienmentioning

confidence: 99%

Disruption of the transcription factorNEUROD2causes an autism syndrome via cell-autonomous defects in cortical projection neurons

Runge¹,

Mathieu²,

Bugeon³

et al. 2018

Preprint

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Abstract:The transcription factor NeuroD2 is a recent candidate for neuropsychiatric disorders but its impact in cortical networks and associated behaviors remains unknown. Here we show that in the mouse neocortex, NeuroD2 is restricted to pyramidal neurons, from development to adulthood. In NeuroD2 deficient mice, layer 5 pyramidal neurons of motor area displayed reduced dendritic complexity and reduced spine density. In contrast, production, radial migration, laminar organization and axonal target specificity of pyramidal neurons were normal, revealing a synaptopathy phenotype. Electrophysiologically, intrinsic excitability and inhibitory inputs onto pyramidal neurons were increased. Behaviorally, NeuroD2 homozygous and heterozygous mice exhibited normal interest and memory for objects but altered sociability and social memory, stereotypies, spontaneous epilepsy and hyperactivity.RNA sequencing from microdissected neocortex revealed that NeuroD2 target genes are highly associated with in cell intrinsic excitability, synaptic regulation, autism and schizophrenia. These results strongly reinforce the potential implication of NeuroD2 mutations in human neuropsychiatric disorders.

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“…Recent genome-wide transcriptome analyses of isolated converted neurons have demonstrated that, as in pancreatic β-cell conversion, converted neuron-like cells are not identical to endogenous neurons (Li et al, 2014; Ye et al, 2015). It is likely that the surrounding microenvironment/niche plays a key role in the maturation of converted cells.…”

Section: Regeneration In Non-mammalian Vertebrates and Other Mammamentioning

confidence: 99%

Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development?

Zheng

Zuo

2017

Hearing Research

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Noise-induced hearing loss (NIHL) affects a large number of military personnel and civilians. Regenerating inner-ear cochlear hair cells (HCs) is a promising strategy to restore hearing after NIHL. In this review, we first summarize recent transcriptome profile analysis of zebrafish lateral lines and chick utricles where spontaneous HC regeneration occurs after HC damage. We then discuss recent studies in other mammalian regenerative systems such as pancreas, heart and central nervous system. Both spontaneous and forced HC regeneration occurs in mammalian cochleae in vivo involving proliferation and direct lineage conversion. However, both processes are inefficient and incomplete, and decline with age. For direct lineage conversion in vivo in cochleae and in other systems, further improvement requires multiple factors, including transcription, epigenetic and trophic factors, with appropriate stoichiometry in appropriate architectural niche. Increasing evidence from other systems indicates that the molecular paths of direct lineage conversion may be different from those of normal developmental lineages. We therefore hypothesize that HC regeneration does not have to follow HC development and that epigenetic memory of supporting cells influences the HC regeneration, which may be a key to successful cochlear HC regeneration. Finally, we discuss recent efforts in viral gene therapy and drug discovery for HC regeneration. We hope that combination therapy targeting multiple factors and epigenetic signaling pathways will provide promising avenues for HC regeneration in humans with NIHL and other types of hearing loss.

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Instructing Perisomatic Inhibition by Direct Lineage Reprogramming of Neocortical Projection Neurons

Cited by 59 publications

References 42 publications

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

Disruption of the transcription factorNEUROD2causes an autism syndrome via cell-autonomous defects in cortical projection neurons

Cochlear hair cell regeneration after noise-induced hearing loss: Does regeneration follow development?

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