Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding

Han, Sisu; Okawa, Satoshi; Wilkinson, Grey; Ghazale, Hussein; Adnani, Lata; Dixit, Rajiv; Tavares, Lígia; Faisal, Imrul; Brooks, Matthew; Cortay, Véronique; Zinyk, Dawn; Sivitilli, Adam; Li, Saiqun; Malik, Faizan; Ilnytskyy, Yaroslav; Angarica, Vladimir Espinosa; Gao, Jinghua; Chinchalongporn, Vorapin; Oproescu, Ana-Maria; Vasan, Lakshmy; Touahri, Yacine; David, Luke Ajay; Raharjo, Eko; Kim, Jung-Woong; Wu, Wei; Rahmani, Waleed; Chan, Jennifer A.; Kovalchuk, Igor; Attisano, Liliana; Kurrasch, Deborah M.; Dehay, Colette; Swaroop, Anand; Castro, Diogo S.; Biernaskie, Jeff; Sol, Antonio del; Schuurmans, Carol

doi:10.1016/j.neuron.2021.07.007

Cited by 33 publications

(41 citation statements)

References 107 publications

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“…A second cleavage by γ-secretase then releases the intracellular domain, NICD, which forms a complex with a DNA-binding transcription factor and a co-activator to regulate transcription of target genes. In many developmental processes, Notch activation occurs contemporaneously with morphological changes which could modulate pathway activity so that signaling and tissue rearrangements are coordinated ( Paolini et al, 2021 ; Han et al, 2021 ; Engel-Pizcueta and Pujades, 2021 ; Lloyd-Lewis et al, 2019 ). For example, cell shape or tension changes in the neighboring cells could impact on the forces exerted on the receptor to alter the amount of cleavage ( Shaya et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Notch-dependent and -independent transcription are modulated by tissue movements at gastrulation

Falo‐Sanjuan

Bray

2022

eLife

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Cells sense and integrate external information from diverse sources that include mechanical cues. Shaping of tissues during development may thus require coordination between mechanical forces from morphogenesis and cell-cell signalling to confer appropriate changes in gene expression. By live-imaging Notch-induced transcription in real time we have discovered that morphogenetic movements during Drosophila gastrulation bring about an increase in activity-levels of a Notch responsive enhancer. Mutations that disrupt the timing of gastrulation resulted in concomitant delays in transcription up-regulation that correlated with the start of mesoderm invagination. As a similar gastrulation-induced effect was detected when transcription was elicited by the intracellular domain NICD, it cannot be attributed to forces exerted on Notch receptor activation. A Notch independent vnd enhancer also exhibited a modest gastrulation-induced activity increase in the same stripe of cells. Together, these observations argue that gastrulation-associated forces act on the nucleus to modulate transcription levels. This regulation was uncoupled when the complex linking the nucleoskeleton and cytoskeleton (LINC) was disrupted, indicating a likely conduit. We propose that the coupling between tissue level mechanics, arising from gastrulation, and enhancer activity represents a general mechanism for ensuring correct tissue specification during development and that Notch dependent enhancers are highly sensitive to this regulation.

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Section: Introductionmentioning

confidence: 99%

Notch-dependent and -independent transcription are modulated by tissue movements at gastrulation

Falo‐Sanjuan

Bray

2022

eLife

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“…Regardless of how Ascl1 and Ascl1 SA 6 function during neuronal reprogramming, astrocytic suppression by the proneural bHLH TFs Neurog2 and Ascl1 has been firmly established in the embryonic CNS ( Oproescu et al, 2021 ). Indeed, embryonic cortical progenitors have a reduced propensity to differentiate into astrocytes, based on in vitro differentiation assays or in vivo lineage tracing ( Han et al, 2021 ). We thus favor the model that Ascl1 SA 6 can both suppress astrocytic gene expression and transactivate neuronal genes more efficiently than Ascl1, as we showed definitively in the embryonic brain ( Li et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Ascl1 phospho-site mutations enhance neuronal conversion of adult cortical astrocytes in vivo

et al. 2022

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Direct neuronal reprogramming, the process whereby a terminally differentiated cell is converted into an induced neuron without traversing a pluripotent state, has tremendous therapeutic potential for a host of neurodegenerative diseases. While there is strong evidence for astrocyte-to-neuron conversion in vitro, in vivo studies in the adult brain are less supportive or controversial. Here, we set out to enhance the efficacy of neuronal conversion of adult astrocytes in vivo by optimizing the neurogenic capacity of a driver transcription factor encoded by the proneural gene Ascl1. Specifically, we mutated six serine phospho-acceptor sites in Ascl1 to alanines (Ascl1SA6) to prevent phosphorylation by proline-directed serine/threonine kinases. Native Ascl1 or Ascl1SA6 were expressed in adult, murine cortical astrocytes under the control of a glial fibrillary acidic protein (GFAP) promoter using adeno-associated viruses (AAVs). When targeted to the cerebral cortex in vivo, mCherry+ cells transduced with AAV8-GFAP-Ascl1SA6-mCherry or AAV8-GFAP-Ascl1-mCherry expressed neuronal markers within 14 days post-transduction, with Ascl1SA6 promoting the formation of more mature dendritic arbors compared to Ascl1. However, mCherry expression disappeared by 2-months post-transduction of the AAV8-GFAP-mCherry control-vector. To circumvent reporter issues, AAV-GFAP-iCre (control) and AAV-GFAP-Ascl1 (or Ascl1SA6)-iCre constructs were generated and injected into the cerebral cortex of Rosa reporter mice. In all comparisons of AAV capsids (AAV5 and AAV8), GFAP promoters (long and short), and reporter mice (Rosa-zsGreen and Rosa-tdtomato), Ascl1SA6 transduced cells more frequently expressed early- (Dcx) and late- (NeuN) neuronal markers. Furthermore, Ascl1SA6 repressed the expression of astrocytic markers Sox9 and GFAP more efficiently than Ascl1. Finally, we co-transduced an AAV expressing ChR2-(H134R)-YFP, an optogenetic actuator. After channelrhodopsin photostimulation, we found that Ascl1SA6 co-transduced astrocytes exhibited a significantly faster decay of evoked potentials to baseline, a neuronal feature, when compared to iCre control cells. Taken together, our findings support an enhanced neuronal conversion efficiency of Ascl1SA6 vs. Ascl1, and position Ascl1SA6 as a critical transcription factor for future studies aimed at converting adult brain astrocytes to mature neurons to treat disease.

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“…Different transcription factor families have been found to serially control distinct steps in the differentiation of neural progenitor cells into neurons, ranging from neural patterning, progenitor specification, proneural induction, neuronal identity establishment, and maintenance ( 15 , 40 ). For example, homeobox proteins such as Pax6, Nkx2.1, and Rax regulate the patterning of neural primordium in different brain regions, whereas basic helix-loop-helix proteins such as Ascl1 and Neurog2 act as proneural genes to drive neuronal differentiation and contribute to neuronal identity establishment ( 15 , 41 – 43 ). However, little is known about the role of T-box family in neuronal fate acquisition and specification.…”

Section: Discussionmentioning

confidence: 99%

Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset

et al. 2022

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The neuroendocrine system consists of a heterogeneous collection of neuropeptidergic neurons in the brain, among which hypothalamic KNDy neurons represent an indispensable cell subtype controlling puberty onset. Although neural progenitors and neuronal precursors along the cell lineage hierarchy adopt a cascade diversification strategy to generate hypothalamic neuronal heterogeneity, the cellular logic operating within the lineage to specify a subtype of neuroendocrine neurons remains unclear. As human genetic studies have recently established a link between TBX3 mutations and delayed puberty onset, we systematically studied Tbx3-derived neuronal lineage and Tbx3-dependent neuronal specification and found that Tbx3 hierarchically established and maintained the identity of KNDy neurons for triggering puberty. Apart from the well-established lineage-dependent fate determination, we uncovered rules of interlineage interaction and intralineage retention operating through neuronal differentiation in the absence of Tbx3. Moreover, we revealed that human TBX3 mutations disturbed the phase separation of encoded proteins and impaired transcriptional regulation of key neuropeptides, providing a pathological mechanism underlying TBX3-associated puberty disorders.

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Proneural genes define ground-state rules to regulate neurogenic patterning and cortical folding

Cited by 33 publications

References 107 publications

Notch-dependent and -independent transcription are modulated by tissue movements at gastrulation

Notch-dependent and -independent transcription are modulated by tissue movements at gastrulation

Ascl1 phospho-site mutations enhance neuronal conversion of adult cortical astrocytes in vivo

Hierarchical deployment of Tbx3 dictates the identity of hypothalamic KNDy neurons to control puberty onset

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