Temporal progression of Drosophila medulla neuroblasts generates the transcription factor combination to control T1 neuron morphogenesis

Naidu, Vamsikrishna G.; Zhang, Y; Lowe, Scott; Ray, Alokananda; Zhu, Hailun; Li, Xin

doi:10.1016/j.ydbio.2020.05.005

Cited by 21 publications

(10 citation statements)

References 32 publications

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“…For ellipsoid body neurons, Grain (grn) and Dichaete (D) emerged as key regulators 48 . In T1 neurons, we identified Ets65A 40 , and Ocelliless (oc) as main regulators 49 and combinations of Acj6, Fkh, TfAP-2, and SoxN/Sox102F in the other T-neurons 2,4,27,40 . Glial cells show repo and Kay expression, and their respective motifs are enriched in glial DARs 50 .…”

Section: Concordant Tf Expression Enhancer Accessibility and Gene Exp...mentioning

confidence: 99%

Decoding gene regulation in the fly brain

Janssens

Aibar

Taskiran

et al. 2022

Nature

125

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The Drosophila brain is a work horse in neuroscience. Single-cell transcriptome analysis 1-5 , 3D morphological classification 6 , and detailed EM mapping of the connectome 7-10 have revealed an immense diversity of neuronal and glial cell types that underlie the wide array of functional and behavioral traits in the fruit fly. The identities of these cell types are controlled by -still unknowngene regulatory networks (GRNs), involving combinations of transcription factors that bind to genomic enhancers to regulate their target genes. To characterize the GRN for each cell type in the Drosophila brain, we profiled chromatin accessibility of 240,919 single cells spanning nine developmental timepoints, and integrated this data with single-cell transcriptomes. We identify more than 95,000 regulatory regions that are used in different neuronal cell types, of which around 70,000 are linked to specific developmental trajectories, involving neurogenesis, reprogramming and maturation. For 40 cell types, their uniquely accessible regions could be associated with their expressed transcription factors and downstream target genes, through a combination of motif discovery, network inference techniques, and deep learning. We illustrate how these "enhancer-GRNs" can be used to reveal enhancer architectures leading to a better understanding of neuronal regulatory diversity. Finally, our atlas of regulatory elements can be used to design genetic driver lines for specific cell types at specific timepoints, facilitating the characterization of brain cell types and the manipulation of brain function. MainThe brain consists of a myriad of different neuronal and glial types, each unique in their morphology and function. The Drosophila brain, which contains around 100,000 cells, is uniquely positioned as a model in which the diversity of brain cell types can be investigated. Recent advances in electron microscopy have allowed the creation of connectome maps of the different regions in the Drosophila brain 7-10 , while the availability of genetic driver lines 11 provides genetic access to many cell types for understanding neuronal function 12 . Furthermore, this diversity of cell types has been bolstered by single-cell transcriptomics on the adult brain 1-5 , the larval brain [13][14][15] , and the ventral nerve cord 16 . The recent development of single-cell assay for transposase accessible chromatin by sequencing (scATAC-seq), makes it possible to measure chromatin accessibility of single cells in high throughput 17,18 , providing an additional crucial layer of information underlying neuronal identity: which genomic regions encode the regulatory information to create and maintain each cell type. The integrated analysis of transcriptomics and chromatin accessibility makes it then possible to jointly study enhancers and gene expression to discover precise regulatory programs across cell types [19][20][21] .Cell type identity is defined by the activity of GRNs in which combinations of transcription factors activate or repress target genes....

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Section: Concordant Tf Expression Enhancer Accessibility and Gene Exp...mentioning

confidence: 99%

Decoding gene regulation in the fly brain

Janssens

Aibar

Taskiran

et al. 2022

Nature

125

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“…Next, we tested Scro's effect on the neuron fate generated in the Slp temporal window. Sox102F is a transcription factor expressed in subsets of neuronal progeny of the Slp stage and D stage NBs (Figure S4A), and it is lost in slp mutant clones 40 . In scro RNAi clones, Sox102F + neurons were also largely lost, showing that Scro is required for the neuron fate generated in the Slp stage (Figure 4E,E').…”

Section: Scro Is Required To Promote Slp Expression To the Threshold Level For Temporal Transitionmentioning

confidence: 99%

“…Previous studies showed that medulla NBs sequentially express Homothorax (Hth), Kumpfuss (Klu), Eyeless (Ey), Sloppy paired (Slp), Dichaete (D) and Tailless (Tll) as they age 18,19 . Among them, Hth, Ey, Slp and D are each required for the expression of the corresponding neuronal transcription factors to control neural fates, but loss of Klu caused a NB proliferation defect, precluding examination of neural fates 18,19,40 . Similar to vertebrate retinal and cortical progenitors, medulla NBs switch to gliogenesis at the end of the lineage and then exit the cell cycle 18,41 .…”

Section: Introductionmentioning

confidence: 99%

A comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing

Zhu

et al. 2021

Preprint

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During development, neural stem cells are temporally patterned to sequentially generate a variety of neural types before exiting the cell cycle. Temporal patterning is well-studied in Drosophila, where neural stem cells called neuroblasts sequentially express cascades of Temporal Transcription Factors (TTFs) to control the birth-order dependent neural specification. However, currently known TTFs were mostly identified through candidate approaches and may not be complete. In addition, many fundamental questions remain concerning the TTF cascade initiation, progression, and termination. It is also not known why temporal progression only happens in neuroblasts but not in their differentiated progeny. In this work, we performed single-cell RNA sequencing of Drosophila medulla neuroblasts of all ages to study the temporal patterning process with single-cell resolution. Our scRNA-seq data revealed that sets of genes involved in different biological processes show high to low or low to high gradients as neuroblasts age. We also identified a list of novel TTFs, and experimentally characterized their roles in the temporal progression and neural fate specification. Our study revealed a comprehensive temporal gene network that patterns medulla neuroblasts from start to end. Furthermore, we found that the progression and termination of this temporal cascade also require transcription factors differentially expressed along the differentiation axis (neuroblasts -> -> neurons). Lola proteins function as a speed modulator of temporal progression in neuroblasts; while Nerfin-1, a factor required to suppress de-differentiation in post-mitotic neurons, acts at the final temporal stage together with the last TTF of the cascade, to promote the switch to gliogenesis and the cell cycle exit. Our comprehensive study of the medulla neuroblast temporal cascade illustrated mechanisms that might be conserved in the temporal patterning of neural stem cells.

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“…1d, e). Moreover, using molecular markers, we found Tm5a/b (Ap+, Toy+, and Sox102F+) 43,44 do not express Unc-5 (Supplementary Fig. 1f).…”

Section: Resultsmentioning

confidence: 94%

Netrins and receptors control Drosophila optic lobe organization and transmedullary neuron axon targeting

Lowe

2021

Preprint

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During development, integration of temporal patterning and spatial patterning of neural progenitors as well as Notch-dependent binary fate choice between sister neurons contribute to generation of neural diversity. How these upstream neural fate specification programs regulate downstream effector genes to control axon targeting and neuropil assembly remains less well-understood. Here we show that Notch-dependent binary fate choice in Drosophila medulla neurons regulates the expression of Netrin, and that Netrin pathway controls axon guidance of transmedullary (Tm) neurons and contributes to the organization of optic lobe neuropils. Netrins are enriched in the lobula where Tm axons target, and the attractive receptor Frazzled is expressed broadly in medulla neurons, while the repulsive receptor Unc-5 is excluded from Tm neurons and this is necessary for their correct targeting to the lobula. Frazzled is required collectively in a group of early-born Tm neurons to establish the inner optic chiasm (IOC) through which Tm axons target lobula. In addition, Frazzled acts in the layer-specific targeting step of Tm3 and Tm4 cell-autonomously, and is also required for the formation of the lobula branch of TmY3. Moreover, we show that the diffusibility of Netrins is necessary for Netrin enrichment in the lobula, the IOC formation and layer-specific targeting of Tm3 and Tm4. Netrin enrichment in the lobula is promoted by Frazzled expressed in Tm neurons, while Unc-5 appears to have an opposite role in Netrin distribution. Furthermore, we show that Netrin B is expressed in the Notch-on hemilineage of medulla neurons including most Tm and TmY neurons that target lobula, and loss of Su(H) abolished NetB expression in the medulla. Without medulla-originated NetB, Tm axons from late-born medulla columns cannot join the IOC. Therefore, the Notch-dependent binary fate choice regulates the assembly of the optic lobe neuropils by controlling the expression of Netrin.

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Temporal progression of Drosophila medulla neuroblasts generates the transcription factor combination to control T1 neuron morphogenesis

Cited by 21 publications

References 32 publications

Decoding gene regulation in the fly brain

Decoding gene regulation in the fly brain

A comprehensive temporal patterning gene network in Drosophila medulla neuroblasts revealed by single-cell RNA sequencing

Netrins and receptors control Drosophila optic lobe organization and transmedullary neuron axon targeting

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