Dedifferentiation‐derived neural stem cells exhibit perturbed temporal progression

• Published in: EMBO reports 2023-06, Vol.24 (6), p.e55837-n/a
• Main Authors: Veen, Kellie, Nguyen, Phuong‐Khanh, Froldi, Francesca, Dong, Qian, Alvarez‐Ochoa, Edel, Harvey, Kieran F, McMullen, John PD, Marshall, Owen, Jusuf, Patricia R, Cheng, Louise Y
• Format: Article
• Language: English
• Subjects: Binding; Cell cycle; Cell Differentiation - genetics; dedifferentiation; Differentiation; Drosophila; Drosophila Proteins - genetics; EMBO11; EMBO27; EMBO34; Gene expression; Gene Expression Regulation, Developmental; Glial cells; Helix-loop-helix proteins (basic); Life Sciences; Neural stem cells; Neural Stem Cells - metabolism; neuroblast; Neuroglia; Neuronal-glial interactions; Neurons; Neurons - metabolism; Reversion; Stem cells; temporal transcription factors; terminal differentiation; Transcription factors; Transcription Factors - metabolism
• ISSN: 1469-221X; 1469-3178
• DOI: 10.15252/embr.202255837

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. Synopsis Dedifferentiated neural stem cells show aberrant expression of temporal transcription factors, resulting in incorrect types of neurons produced and impaired terminal differentiation. This has important ramifications for the utilisation of dedifferentiated stem cells for regenerative purposes. Dedifferentiation induced by the overexpression of Deadpan, Nerfin‐1 loss of function and Lola knockdown generates NSC with aberrant expression of temporal transcription factors. Dedifferentiated neural stem cells make incorrect types of neurons and fail to undergo appropriate temporal progression. Deadpan specifically binds to the mid‐temporal transcription factors. Restoration of temporal progression can be triggered by promoting the expression of cell cycle factors or the subsequent temporal transcription factor. Graphical Abstract Dedifferentiated neural stem cells show aberrant expression of temporal transcription factors, resulting in incorrect types of neurons produced and impaired terminal differentiation. This has important ramifications for the utilisation of dedifferentiated stem cells for regenerative purposes.