Dedifferentiation‐derived neural stem cells exhibit perturbed temporal progression

Veen, Kellie; Nguyen, Phuong-Khanh; Froldi, Francesca; Dong, Qian; Alvarez-Ochoa, Edel; Harvey, Ken; McMullen, John P D; Marshall, Owen J.; Jusuf, Patricia Regina; Cheng, Louise

doi:10.15252/embr.202255837

Cited by 3 publications

(4 citation statements)

References 52 publications

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“…Immunostainings showed that EcR is expressed at very low levels in the medulla NBs at 12 hr APF (Supplementary Figure 1A). Additionally, when EcR was knocked down via RNAi in the medulla NBs with eyR16F10-GAL4, which is expressed in a subset of medulla NBs and their progeny (Veen et al , 2023), we could not detect any persistent NBs at 24 hr APF (Supplementary Figure 1B, C, E). A similar phenotype was observed using a dominant negative form of EcR (EcR DN ) (Supplementary Figure 1D, E).…”

Section: Resultsmentioning

confidence: 93%

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Neuroepithelial depletion schedules cessation of neurogenesis in theDrosophilaoptic lobes

Nguyen,

Cheng

2023

Preprint

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The brain is consisted of diverse neurons arising from a limited number of neural stem cells.Drosophilaneural stem cells called neuroblasts (NBs) produces specific neural lineages of various lineage sizes depending on their location in the brain. In theDrosophilavisual processing centre – the optic lobes (OLs), medulla NBs derived from the neuroepithelium (NE) give rise to neurons and glia cells of the medulla cortex. The timing and the mechanisms responsible for the cessation of medulla NBs are so far not known. In this study, we show that the termination of medulla NBs during pupal development is determined by the exhaustion of the NE stem cell pool. Altering NE-NB transition during larval neurogenesis disrupts the timely termination of medulla NBs. Medulla NBs terminate neurogenesis via a combination of cell death, terminal symmetric division, and a switch to gliogenesis. We show that temporal progression is not required for the termination of medulla NBs. The timing of NB cessation can be altered through the acquisition of a glial cell fate via Glial cells missing, or through conversion to type II NB cell fate via Tailless, or by inhibition of differentiation via Prospero knockdown. As theDrosophilaOL shares a similar mode of division with mammalian neurogenesis, determining how and when these progenitors cease proliferation during development can have important implications for mammalian brain size determination and regulation of its overall function.

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Section: Resultsmentioning

confidence: 93%

“…Wildtype fly was w 1118 . eyR16F10-GAL4 (BL 48737) was used to induce expression of transgenes in a subset of medulla NBs and their progeny from larval development (Veen et al , 2023). Knockdown and overexpression clones were induced by flip-out system using hsFLP,act>CD2>GAL4;UAS-Dcr2,UAS-GFP (a gift from Lei Zhang).…”

Section: Methodsmentioning

confidence: 99%

Neuroepithelial depletion schedules cessation of neurogenesis in theDrosophilaoptic lobes

Nguyen,

Cheng

2023

Preprint

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“…Dpn is expressed in NBs and necessary for the maintenance of NB 'stemness' (San-Jua ´n annbd Baonza 2011), and more recently, we have shown that Dpn overexpression is sufficient to induce neuron to NB dedifferentiation [24]. The zebrafish ortholog of dpn, her6, is expressed in developmental progenitors within the inner nuclear layer (INL) and is downregulated upon neurogenesis [27].…”

Section: Plos Geneticsmentioning

confidence: 99%

“…In future studies, it would be interesting to test whether the loss of Her6 can stimulate quiescent MG to re-enter cell cycle in the absence injury. Drosophila ortholog of her6, deadpan (dpn), is also a Notch target gene, however, it plays an opposite function within neurons, where the overexpression of Dpn triggers the transition of mature neurons to NSCs [24]. Together, this highlights the dynamic roles of Notch signalling in different cell types.…”

Section: Her6 In Regenerationmentioning

confidence: 99%

Her6 and Prox1a are novel regulators of photoreceptor regeneration in the zebrafish retina

Veen,

Krylov,

et al. 2023

PLoS Genet

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Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, can regenerate PRs efficiently and restore functional vision. Upon injury, mature Müller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors. prospero homeobox 1a (prox1a) is expressed in differentiated PRs and may promote PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1a is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1a also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other; these may be exploited to promote human retinal regeneration and vision recovery.

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Dedifferentiation‐derived neural stem cells exhibit perturbed temporal progression

et al. 2023

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Dedifferentiation is the reversion of mature cells to a stem cell‐like fate, whereby gene expression programs are altered and genes associated with multipotency are (re)expressed. Misexpression of multipotency factors and pathways causes the formation of ectopic neural stem cells (NSCs). Whether dedifferentiated NSCs faithfully produce the correct number and types of progeny, or undergo timely terminal differentiation, has not been assessed. Here, we show that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression fail to undergo appropriate temporal progression by constantly expressing mid‐temporal transcription factor(tTF), Sloppy‐paired 1/2 (Slp). Consequently, this resulted in impaired terminal differenation and generated an excess of Twin of eyeless (Toy)‐positive neurons at the expense of Reversed polarity (Repo)‐positive glial cells. Preference for a mid‐temporal fate in these ectopic NSCs is concordant with an enriched binding of Dpn at mid‐tTF loci and a depletion of Dpn binding at early‐ and late‐tTF loci. Retriggering the temporal series via manipulation of the temporal series or cell cycle is sufficient to reinstate neuronal diversity and timely termination.

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Dedifferentiation‐derived neural stem cells exhibit perturbed temporal progression

Cited by 3 publications

References 52 publications

Neuroepithelial depletion schedules cessation of neurogenesis in theDrosophilaoptic lobes

Neuroepithelial depletion schedules cessation of neurogenesis in theDrosophilaoptic lobes

Her6 and Prox1a are novel regulators of photoreceptor regeneration in the zebrafish retina

Dedifferentiation‐derived neural stem cells exhibit perturbed temporal progression

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