Drosophila as a "3Rs" (Replace, Reduce and Refine) model system is emphasized in a study with potential relevance to neurodegenerative disease

Gonçalves-Pimentel C, Mazaud D, Kottler B, Proelss S, Hirth F, Fanto M. A miRNA screen procedure identifies garz as an essential factor in adult glia functions and validates Drosophila as a beneficial 3Rs model to study glial functions and GBF1 biology. F1000Res. 2020 May 1;9:317. doi:
10.12688/f1000research.23154.2. PMID: 32595956; PMCID: PMC7309417.

 

Abstract:

"Invertebrate glia performs most of the key functions controlled by mammalian glia in the nervous system and provides an ideal model for genetic studies of glial functions. To study the influence of adult glial cells in ageing we have performed a genetic screen in Drosophila using a collection of transgenic lines providing conditional expression of micro-RNAs (miRNAs). Here, we describe a methodological algorithm to identify and rank genes that are candidate to be targeted by miRNAs that shorten lifespan when expressed in adult glia. We have used four different databases for miRNA target prediction in Drosophila but find little agreement between them, overall. However, top candidate gene analysis shows potential to identify essential genes involved in adult glial functions. One example from our top candidates' analysis is gartenzwerg ( garz). We establish that garz is necessary in many glial cell types, that it affects motor behaviour and, at the sub-cellular level, is responsible for defects in cellular membranes, autophagy and mitochondria quality control. We also verify the remarkable conservation of functions between garz and its mammalian orthologue, GBF1, validating the use of Drosophila as an alternative 3Rs-beneficial model to knock-out mice for studying the biology of GBF1, potentially involved in human neurodegenerative diseases."

Establishment of a "multi-species high-throughput platform" to evaluate candidate congential heart disease genes

Theis JL, Vogler G, Missinato MA, Li X, Nielsen T, Zeng XI, Martinez- Fernandez A, Walls SM, Kervadec A, Kezos JN, Birker K, Evans JM, O'Byrne MM, Fogarty ZC, Terzic A, Grossfeld P, Ocorr K, Nelson TJ, Olson TM, Colas AR, Bodmer R. Patient-specific genomics and cross-species functional analysis implicate LRP2 in hypoplastic left heart syndrome. Elife. 2020 Oct 2;9:e59554.
doi: 10.7554/eLife.59554. Epub ahead of print. PMID: 33006316.

 

From the abstract:

"Congenital heart diseases (CHDs) ... are genetically complex and poorly understood. Here, a multi-disciplinary platform was established to functionally evaluate novel CHD gene candidates, based on whole genome and iPSC RNA sequencing of a HLHS family-trio. ... siRNA/RNAi-mediated knockdown in generic human iPSC-derived cardiomyocytes (hiPSC-CM) and in developing Drosophila and zebrafish hearts revealed that LDL receptor-related protein LRP2 is required for cardiomyocyte proliferation and differentiation. ... Collectively, we have established a multi-species high-throughput platform to rapidly evaluate candidate genes and their interactions during heart development, which are crucial first steps towards deciphering oligogenic underpinnings of CHDs, including maladaptive left hearts."

Article discusses potential use of Drosophila in COVID-19 / SARS-CoV-2 related studies

Front Pharmacol. 2020; 11: 588561.

Potential Application of Drosophila melanogaster as a Model Organism in COVID-19-Related Research
Firzan Nainu, Dini Rahmatika, Talha Bin Emran, and Harapan Harapan

Published online 2020 Sep 4. doi: 10.3389/fphar.2020.588561

[No abstract]

PMCID: PMC7500409
PMID: 33013425

Click here to access the article at PubMed Central.

'Humanized' Drosophila Model of Meier-Gorlin Syndrome

Humanized Drosophila Model of the Meier-Gorlin Syndrome Reveals Conserved and Divergent Features of the Orc6 Protein

Maxim Balasov, Katarina Akhmetova and Igor Chesnokov
Genetics Early online October 9, 2020

https://doi.org/10.1534/genetics.120.303698

Abstract:

Meier-Gorlin syndrome (MGS) is a rare autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears and skeletal abnormalities. Patients with MGS often carry mutations in genes encoding the subunits of the Origin Recognition Complex (ORC), components of the pre-replicative complex (pre-RC) and replication machinery. Orc6 is an important component of ORC and has functions in both DNA replication and cytokinesis. A mutation in the conserved C-terminal motif of Orc6 associated with MGS impedes the interaction of Orc6 with core ORC. Recently, a new mutation in Orc6 was also identified however, it is localized in the N-terminal domain of the protein. In order to study the functions of Orc6 we used the human gene to rescue the orc6 deletion in Drosophila. Using this "humanized" Orc6-based Drosophila model of the Meier-Gorlin syndrome we discovered that unlike the previous Y225S MGS mutation in Orc6, the K23E substitution in the N-terminal TFIIB-like domain of Orc6 disrupts the protein ability to bind DNA. Our studies revealed the importance of evolutionarily conserved and variable domains of Orc6 protein and allowed the studies of human protein functions and the analysis of the critical amino acids in live animal heterologous system as well as provided novel insights into the mechanisms underlying MGS pathology.