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Dedifferentiation-derived neural stem cells exhibit perturbed temporal progression

ABSTRACT: 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 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 (Slp-1). 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 NBs is concordant with an enriched binding of Dpn at mid-tTF loci and a depletion of Dpn binding at early and late tTF loci. Re-triggering the temporal series via manipulatsion of the temporal series or cell cycle is sufficient to reinstate neuronal diversity and timely termination.

SUBMITTER: Ms. Kellie Veen

PROVIDER: S-SCDT-10_15252-EMBR_202255837 | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:One of the key regulatory mechanisms of brain size and neuronal diversity is through control of NB identity via cell fate maintenance. Dedifferentiation is the reversion of differentiated cells to a stem cell like fate, whereby, the gene expression program of mature cells is altered and genes associated with multipotency are expressed. Beyond the fact that misexpression of these factors and pathways caused the formation of ectopic NBs, whether these dedifferentiated NBs faithfully produce the correct number and types of neurons or glial cells, or undergo timely terminal differentiation, has not been assessed. These characteristics are key determinants of overall CNS size and function, thus are important parameters when considering whether dedifferentiation leads to tumourigenesis or can be appropriately utilized for regenerative purposes. Appropriate terminal differentiation as well as neuronal diversity are key characteristics of NSCs, and are specified through temporal patterning of the NSCs driven by the successive expression of temporal transcription factors (tTFs). In this study, we found that ectopic NSCs induced via bHLH transcription factor Deadpan (Dpn) expression in the optic lobes of the developing Drosophila CNS fail to undergo appropriate temporal progression, where they express mid-tTF, Sloppy-paired 1 (Slp-1) at the expense of late-tTF Tailless (Tll); consequently generating an excess of Twin of eyeless (Toy) positive neurons and fewer Reversed polarity (Repo) positive glial cells. Dpn overexpression also resulted in stalled progression through the cell cycle, and a failure to undergo timely terminal differentiation. Mechanistically, DamID studies demonstrated that Dpn directly binds to both Dichaete (D), a Sox-box transcription factor known to repress Slp-1, as well as a number of cell cycle genes. Promoting cell cycle progression or overexpression of D were able to re-trigger the progression of the temporal series in dedifferentiated NBs, restoring both neuronal diversity and timely NB terminal differentiation.

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Dedifferentiation-derived neural stem cells exhibit perturbed temporal progression

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