A novel Drosophila model for neurodevelopmental disorders associated with Shwachman–Diamond syndrome

Takai, Akari; Chiyonobu, Tomohiro; Ueoka, Ibuki; Tanaka, Ryo; Tozawa, Takenori; Yoshida, Hideki; Morimoto, Masafumi; Hosoi, Hajime; Yamaguchi, Masamitsu

doi:10.1016/j.neulet.2020.135449

Cited by 9 publications

(4 citation statements)

References 27 publications

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“…This pleads for an impact of a targeted, specific remodelling of niche architecture during development on adult behaviour. Hyperactivity (increased locomotor activity and reduced sleep) in Drosophila has been found in diverse models of neuro/developmental and neurological disorders, including the Fragile X syndrome [62], Attention-deficit/hyperactivity disorder (ADHD) [63] and Shwachman-Diamond syndrome [64]. In all these cases, changes in locomotion were correlated with synaptic and axonal abnormalities.…”

Section: Discussionmentioning

confidence: 99%

A corset of adhesions during development establishes individual neural stem cell niches and controls adult behaviour

Banach-Latapy

Rincheval

Guénal

et al. 2022

Preprint

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Neural stem cells (NSCs) reside in a defined cellular microenvironment, the niche, which supports the generation and integration of neuronal lineages. The mechanisms building a sophisticated niche structure around NSCs, and their functional relevance for neurogenesis are yet to be understood. In the Drosophila larval brain, the cortex glia (CG) encase individual NSC lineages, organizing the stem cell population and newborn neurons into a stereotypic structure. We first found that lineage information is dominant over stem cell fate. We then discovered that, in addition to timing, the balance between multiple adhesion complexes supports the individual encasing of NSC lineages. An intra-lineage adhesion through homophilic Neuroglian interactions provides strong binding between cells of a same lineage, while a weaker interaction through Neurexin-IV exists between CG to NSC lineages. Their loss leads to random, aberrant grouping of several NSC lineages together, and to altered axonal projection of newborn neurons. Further, we link the loss of these two adhesion complexes during development to locomotor hyperactivity in the resulting adults. Altogether, our findings identify a corset of adhesions building a neurogenic niche at the scale of individual stem cell and provide the proof-of-principle that mechanisms supporting niche formation during development define adult behaviour.

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Section: Discussionmentioning

confidence: 99%

A corset of adhesions during development establishes individual neural stem cell niches and controls adult behaviour

Banach-Latapy

Rincheval

Guénal

et al. 2022

Preprint

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“…Next, we used the elav-GAL4 driver 18,23,39 to induce RNAi in all neurons (pan-neuronal), which are postmitotic cells that derive from neuroblasts. This driver is active not only in embryos and larvae, but also in pupae and adults, and pan-neuronal RNAi yielded both developmental and adult phenotypes.…”

Section: Dpolr1d Is Required For Rrna Productionmentioning

confidence: 99%

“…Importantly, while zebrafish and mouse are more appropriate models to study POLR1D function in development, those studies have relied on the use of complete deletions of POLR1D , which precludes the ability to study the molecular consequences and developmental outcomes of TCS disease variants 2,9 . Drosophila is emerging as an excellent model system in which to study ribosomopathies due to the high conservation of ribosome biogenesis factors between flies and humans 17,18 and the availability of reagents to interrogate the function of disease‐associated genes. Most importantly, Drosophila has a long history as a valuable platform for modeling human disease variants 19‐22 …”

Section: Introductionmentioning

confidence: 99%

A clinically‐relevant residue of POLR1D is required for Drosophila development

Palumbo

Belkevich

Pascual

et al. 2022

Developmental Dynamics

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Background: POLR1D is a subunit of RNA Polymerases I and III, which synthesize ribosomal RNAs. Dysregulation of these polymerases cause several types of diseases, including ribosomopathies. The craniofacial disorder Treacher Collins Syndrome (TCS) is a ribosomopathy caused by mutations in several subunits of RNA Polymerase I, including POLR1D. Here, we characterized the effect of a missense mutation in POLR1D and RNAi knockdown of POLR1D on Drosophila development. Results: We found that a missense mutation in Drosophila POLR1D (G30R) reduced larval rRNA levels, slowed larval growth, and arrested larval development. Remarkably, the G30R substitution is at an orthologous glycine in POLR1D that is mutated in a TCS patient (G52E). We showed that the G52E mutation in human POLR1D, and the comparable substitution (G30E) in Drosophila POLR1D, reduced their ability to heterodimerize with POLR1C in vitro. We also found that POLR1D is required early in the development of Drosophila neural cells. Furthermore, an RNAi screen revealed that POLR1D is also required for development of non-neural Drosophila cells, suggesting the possibility of defects in other cell types. Conclusions: These results establish a role for POLR1D in Drosophila development, and present Drosophila as an attractive model to evaluate the molecular defects of TCS mutations in POLR1D.

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“…Many of the genes and pathways identified in human epilepsy are highly conserved in Drosophila 22 . The animal has been used to model other forms of human epilepsy, including Dravet Syndrome and Generalised Epilepsy with Febrile Seizures Plus (GEFS+) due to mutations in the sodium channel gene SCN1A 23,24 and can make powerful tools for therapeutic screens 25 . The majority of KCNT1-epilepsy mutations cluster around three, highly conserved, functional domains in the KCNT1 protein 1 .…”

Section: Introductionmentioning

confidence: 99%

Modelling human KCNT1-epilepsy inDrosophila: a seizure phenotype and drug responses

Dibbens

Ricos

Hussain

et al. 2023

Preprint

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Mutations in the KCNT1 potassium channel cause severe forms of epilepsy which are resistant to current treatments. In vitro studies have shown that KCNT1-epilepsy mutations are gain of function, significantly increasing K+ current amplitudes. To investigate if Drosophila can be used to model human KCNT1 epilepsy, we generated Drosophila melanogaster lines carrying human KCNT1 with the patient mutation G288S, R398Q or R928C. Expression of each mutant channel in GABAergic neurons gave a seizure phenotype which was sensitive to drugs currently used to treat patients with KCNT1-epilepsy. Cannabidiol showed the greatest reduction of the seizure phenotype while some drugs increased the seizure phenotype. Our study shows that Drosophila can be used to model human KCNT1- epilepsy and potentially used as a tool to assess new treatments for KCNT1 epilepsy.

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A novel Drosophila model for neurodevelopmental disorders associated with Shwachman–Diamond syndrome

Cited by 9 publications

References 27 publications

A corset of adhesions during development establishes individual neural stem cell niches and controls adult behaviour

A corset of adhesions during development establishes individual neural stem cell niches and controls adult behaviour

A clinically‐relevant residue of POLR1D is required for Drosophila development

Modelling human KCNT1-epilepsy inDrosophila: a seizure phenotype and drug responses

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