Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors

Chen, Rui; Hou, Yanjun; Connell, Marisa; Zhu, Sijun

doi:10.1371/journal.pgen.1009371

Cited by 14 publications

(12 citation statements)

References 67 publications

(95 reference statements)

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“…Using GFP reporter expression, we confirmed that Six4 is expressed in type II neuroblasts and not in INPs (Supplementary Fig. 7a ) 65 . We further identified a neuroblast-specific Zld-bound region upstream of Six4 that significantly lost chromatin accessibility upon neuroblast differentiation in our time-release system (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 61%

Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila

et al. 2021

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During Drosophila embryogenesis, the essential pioneer factor Zelda defines hundreds of cis-regulatory regions and in doing so reprograms the zygotic transcriptome. While Zelda is essential later in development, it is unclear how the ability of Zelda to define cis-regulatory regions is shaped by cell-type-specific chromatin architecture. Asymmetric division of neural stem cells (neuroblasts) in the fly brain provide an excellent paradigm for investigating the cell-type-specific functions of this pioneer factor. We show that Zelda synergistically functions with Notch to maintain neuroblasts in an undifferentiated state. Zelda misexpression reprograms progenitor cells to neuroblasts, but this capacity is limited by transcriptional repressors critical for progenitor commitment. Zelda genomic occupancy in neuroblasts is reorganized as compared to the embryo, and this reorganization is correlated with differences in chromatin accessibility and cofactor availability. We propose that Zelda regulates essential transitions in the neuroblasts and embryo through a shared gene-regulatory network driven by cell-type-specific enhancers.

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Section: Resultsmentioning

confidence: 61%

Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila

et al. 2021

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“…However, these data could be also explained by changes in the expression of PntP1 as we demonstrated here that there is a positive feedback loop between PntP1 and Tll. For example, the reduction in the Tll expression resulting from Erm overexpression in type II NBs could be due to inhibition of PntP1 by Erm in type II NB as we reported previously [14,51] rather than direct inhibition of Tll by Erm. Furthermore, Erm and Ham are not expressed in the newly generated imINPs, in which Tll expression is already largely suppressed.…”

Section: Plos Geneticsmentioning

confidence: 51%

“…functions as a transcriptional repressor [21,52] as also demonstrated in this study, it is unlikely that Tll directly activates PntP1 expression. Our previous studies suggest that there might be an unknown feedback signal from INPs that could be required for maintaining PntP1 expression [9,51]. Thus, one potential explanation for the loss of PntP1 expression in Tll knockdown type II NBs could be the loss of INPs and their feedback signal resulting from the ectopic Ase expression in type II NBs.…”

Section: Plos Geneticsmentioning

confidence: 99%

The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless

2022

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Intermediate neural progenitors (INPs) boost the number and diversity of neurons generated from neural stem cells (NSCs) by undergoing transient proliferation. In the developing Drosophila brains, INPs are generated from type II neuroblasts (NBs). In order to maintain type II NB identity and their capability to produce INPs, the proneural protein Asense (Ase) needs to be silenced by the Ets transcription factor pointed P1 (PntP1), a master regulator of type II NB development. However, the molecular mechanisms underlying the PntP1-mediated suppression of Ase is still unclear. In this study, we utilized genetic and molecular approaches to determine the transcriptional property of PntP1 and identify the direct downstream effector of PntP1 and the cis-DNA elements that mediate the suppression of ase. Our results demonstrate that PntP1 directly activates the expression of the transcriptional repressor, Tailless (Tll), by binding to seven Ets-binding sites, and Tll in turn suppresses the expression of Ase in type II NBs by binding to two hexameric core half-site motifs. We further show that Tll provides positive feedback to maintain the expression of PntP1 and the identity of type II NBs. Thus, our study identifies a novel direct target of PntP1 and reveals mechanistic details of the specification and maintenance of the type II NB identity by PntP1.

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“…Additionally, the Drosophila integrator complex [ 50 , 51 ] prevents INP dedifferentiation by regulating of Erm [ 52 ]. Recently, it was shown, that Six4 is yet another factor preventing the generation of supernumerary type II neuroblasts through the formation of a trimeric complex with Earmuff and Pointed P1 [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Enhancer analysis of the Drosophila zinc finger transcription factor Earmuff by gene targeting

et al. 2021

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Background Many transcription factors are involved in the formation of the brain during the development of Drosophila melanogaster. The transcription factor Earmuff (Erm), a member of the forebrain embryonic zinc finger family (Fezf), is one of these important factors for brain development. One major function of Earmuff is the regulation of proliferation within type II neuroblast lineages in the brain; here, Earmuff is expressed in intermediate neural progenitor cells (INPs) and balances neuronal differentiation versus stem cell maintenance. Erm expression during development is regulated by several enhancers. Results In this work we show a functional analysis of erm and some of its enhancers. We generated a new erm mutant allele by gene targeting and reintegrated Gal4 to make an erm enhancer trap strain that could also be used on an erm mutant background. The deletion of three of the previously analysed enhancers showing the most prominent expression patterns of erm by gene targeting resulted in specific temporal and spatial defects in defined brain structures. These defects were already known but here could be assigned to specific enhancer regions. Conclusion This analysis is to our knowledge the first systematic analysis of several large enhancer deletions of a Drosophila gene by gene targeting and will enable deeper analysis of erm enhancer functions in the future.

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Homeodomain protein Six4 prevents the generation of supernumerary Drosophila type II neuroblasts and premature differentiation of intermediate neural progenitors

Cited by 14 publications

References 67 publications

Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila

Cell-type-specific chromatin occupancy by the pioneer factor Zelda drives key developmental transitions in Drosophila

The Ets protein Pointed P1 represses Asense expression in type II neuroblasts by activating Tailless

Enhancer analysis of the Drosophila zinc finger transcription factor Earmuff by gene targeting

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