Opportunities lost and gained: Changes in progenitor competence during nervous system development

Farnsworth, Dylan; Doe, Chris Q.

doi:10.1080/23262133.2017.1324260

Cited by 10 publications

(9 citation statements)

References 71 publications

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“…Two distinct neuroblast lineages function together to generate the requisite number of neurons for the development of adult fly brains (Farnsworth and Doe, 2017;Homem et al, 2015;. Similar to ventricular zone neural stem cells, type I neuroblasts undergo direct neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Continual inactivation of genes involved in stem cell functional identity stabilizes progenitor commitment

Quinto-Rives

Komori

Janssens

et al. 2020

Preprint

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Statement Expanding the pool of stem cells that indirectly generate differentiated cell types through intermediate progenitors drives vertebrate brain evolution. Due to lack of lineage information, mechanistic investigation of their competency to generate intermediate progenitors remain impossible. Fly larval brain neuroblasts provide excellent in vivo models for investigating the regulation of stem cell functionality during neurogenesis. Type II neuroblasts undergo indirect neurogenesis by repeatedly dividing asymmetrically to generate a neuroblast and a progeny that commits to an intermediate neural progenitor (INP) identity. We identified Tailless as a unique regulator that maintains type II neuroblast functional identity including the competency to generate INPs. Successive inactivation during INP commitment renders tll refractory to activation by Notch signaling, preventing INPs from re-acquiring neuroblast functionality. We propose that continual inactivation of neural stem cell functional identity genes by histone deacetylation allows intermediate progenitors to stably commit to generate diverse differentiated cell types during indirect neurogenesis.

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Section: Introductionmentioning

confidence: 99%

Continual inactivation of genes involved in stem cell functional identity stabilizes progenitor commitment

Quinto-Rives

Komori

Janssens

et al. 2020

Preprint

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show abstract

“…Two distinct neuroblast lineages function together to generate the number of neurons requisite for the development of adult fly brains ( Farnsworth and Doe, 2017 ; Homem et al, 2015 ; Janssens and Lee, 2014 ). Similar to ventricular zone neural stem cells, type I neuroblasts undergo direct neurogenesis.…”

Section: Introductionmentioning

confidence: 99%

Sequential activation of transcriptional repressors promotes progenitor commitment by silencing stem cell identity genes

Rives-Quinto

Komori

Ostgaard

et al. 2020

eLife

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Stem cells that indirectly generate differentiated cells through intermediate progenitors drives vertebrate brain evolution. Due to a lack of lineage information, how stem cell functionality, including the competency to generate intermediate progenitors, becomes extinguished during progenitor commitment remains unclear. Type II neuroblasts in fly larval brains divide asymmetrically to generate a neuroblast and a progeny that commits to an intermediate progenitor (INP) identity. We identified Tailless (Tll) as a master regulator of type II neuroblast functional identity, including the competency to generate INPs. Successive expression of transcriptional repressors functions through Hdac3 to silence tll during INP commitment. Reducing repressor activity allows re-activation of Notch in INPs to ectopically induce tll expression driving supernumerary neuroblast formation. Knocking down hdac3 function prevents downregulation of tll during INP commitment. We propose that continual inactivation of stem cell identity genes allows intermediate progenitors to stably commit to generating diverse differentiated cells during indirect neurogenesis.

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“…Neuroblasts and INPs undergo successive asymmetric divisions and these divisions act as a clock changing the transcriptional profile of these cells from early stages to late stages (Ren et al 2017;Bayraktar and Doe 2013;Kohwi and Doe 2013;Li et al 2013). As NBs and INPs continue to divide, they lose their capacity to generate early born progeny, a phenomenon termed progressive restriction in competence Farnsworth and Doe 2017). It is possible that as NBs and INPs age, they also lose proliferative potential.…”

Section: Discussionmentioning

confidence: 99%

“…The Drosophila melanogaster larval nervous system is a well-established model for elucidating mechanisms of neurogenesis Homem and Knoblich 2012;Homem et al 2015;Farnsworth and Doe 2017). The ability of stem cells to preserve proliferation while progressively generating more differentiated progeny is achieved through asymmetric divisions, a key feature of neuroblasts (the stem cells of the central nervous system in Drosophila).…”

Section: Introductionmentioning

confidence: 99%

Paralytic, theDrosophilavoltage-gated sodium channel, regulates proliferation of neural progenitors

Piggott

Peters

et al. 2019

Preprint

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Proliferating cells, typically considered "non-excitable," nevertheless exhibit regulation by bioelectrical signals. Notably, voltage-gated sodium channels (VGSC) that are crucial for neuronal excitability, are also found in progenitors and upregulated in cancer. Here, we identify a role for VGSC in proliferation of Drosophila neuroblast (NB) lineages within the central nervous system. Loss of paralytic (para), the sole gene that encodes Drosophila VGSC, reduces neuroblast progeny cell number. The type II neuroblast lineages, featuring a transit-amplifying intermediate neural progenitors (INP) population similar to that found in the developing human cortex, are particularly sensitive to para manipulation. Following a series of asymmetric divisions, INPs normally exit the cell cycle through a final symmetric division. Our data suggests that loss of para induces apoptosis in this population, whereas overexpression leads to an increase in INPs and overall neuroblast progeny cell numbers. These effects are cell autonomous and depend on Para channel activity. Reduction of Para not only affects normal NB development, but also strongly suppresses brain tumor mass, implicating a role for Para in cancer progression. To our knowledge, our studies are the first to identify a role for VGSC in neural progenitor proliferation. Elucidating the contribution of VGSC in proliferation will advance our understanding of bioelectric signaling within development and disease states.

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Opportunities lost and gained: Changes in progenitor competence during nervous system development

Cited by 10 publications

References 71 publications

Continual inactivation of genes involved in stem cell functional identity stabilizes progenitor commitment

Continual inactivation of genes involved in stem cell functional identity stabilizes progenitor commitment

Sequential activation of transcriptional repressors promotes progenitor commitment by silencing stem cell identity genes

Paralytic, theDrosophilavoltage-gated sodium channel, regulates proliferation of neural progenitors

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