ABSTRACT
First Person is a series of interviews with the first authors of a selection of papers published in Disease Models & Mechanisms, helping researchers promote themselves alongside their papers. Arnaud Duchon is first author on ‘ Ts66Yah, a mouse model of Down syndrome with improved construct and face validity’, published in DMM. Arnaud is a PhD research engineer in the lab of Yann Herault at the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch-Graffenstaden, France, investigating trisomy 21 (Down syndrome) with mouse model approaches.
Arnaud Duchon
How would you explain the main findings of your paper to non-scientific family and friends?
My main interest is to understand the mechanisms of intellectual disabilities in Down syndrome (DS). DS is due to the presence of a supernumerary chromosome 21 and is the most common form of intellectual disability. For the study of this syndrome, we have chosen the mouse as a model because it shares some similar biology with human at anatomical, cellular, biochemical and molecular levels. For example, behaviours such as anxiety, aggression, memory and other emotional responses are observed in mouse and rely on brain structures and functions with strong similarities to those of human. At the genetic level, the mouse is close to man, with more than 92% homologous genes. In our study, we investigated the so-called ‘historical’ Ts65Dn mouse model that was identified in the 90s. Ts65Dn mice carry an extra minichromosome generated after irradiation where part of the mouse chromosome 16 homologous to human chromosome 21 is fused to the centromeric region of mouse chromosome 17. This model has been extensively studied in the DS field as it mimics the increase in gene dosage with one additional copy of genes located on part of mouse chromosome 16 homologous to human chromosome 21. More than 500 publications have been reported in the literature, and most of the therapies for DS have been tested on this model. Nevertheless, we found and reported in 2011 that the segment close to the centromere of mouse chromosome 17 on the minichromosome carries more than 40 genes that are also triplicated in the Ts65Dn, but those genes are not homologous to human chromosome 21 genes. Thus, we hypothesized that they can contribute to the phenotypes observed in the model. In the paper, we report the characterization of an updated model, that we call Ts66Yah, in which we used new technology to remove the genes located on the minichromosome from the centromeric region of mouse chromosome 17. This new model corresponds to an increase in gene dosage only for genes homologous to human chromosome 21, and we found some changes at the behavioural and molecular levels in the brain regions involved in learning and memory. Thus, we propose now to the community to select this new model or at least to take into account the genetic limitations of the Ts65Dn model.
What are the potential implications of these results for your field of research?
This new model has been characterized from a morphological, cognitive and physiological point of view in order to highlight the similar defects also found in individuals with DS. It can be used in the future to test new therapeutic pathways as proof of concept before application in humans.
“The major advantage of this new model for studying trisomy 21 is that it has, as in humans, an additional chromosome, which is not the case for other models with segmental duplication.”
What are the main advantages and drawbacks of the experimental system you have used as it relates to the disease you are investigating?
The major advantage of this new model for studying trisomy 21 is that it has, as in humans, an additional chromosome, which is not the case for other models with segmental duplication. Thus, in this new model, the genes present in three copies represent 65% of the genes present on human chromosome 21. The principal drawback is that this model is not a complete DS model but a partial one. This is why it is important, especially for preclinical testing, to use more than one model and to try more complex genetic models.
Mouse models for Down syndrome (DS) are instrumental in understanding the molecular basis of the various clinical features of DS.
What has surprised you the most while conducting your research?
I was very surprised by the impact on DS features of the triplicated genes that were on the centromeric mouse chromosome 17 that are homologous to human chromosome 6 genes. It really showed that additional genes can contribute and enhance DS features even if they are not found on human chromosome 21. The effects observed are more important than one might think at first. This should really be considered in future research.
What do you think is the most significant challenge impacting your research at this time and how will this be addressed over the next 10 years?
Animal models remain essential in the understanding of intellectual diseases and also for the identification of new therapeutic strategies. Ten years ago, no one was talking about therapeutic strategies for DS, and now several studies have highlighted multiple possible signalling pathways based on a DS mouse model. However, despite the fact that preclinical studies have reported an improvement in deficits in mice, clinical trials in humans have shown disappointing results. Having a better model, ensuring a good level of reproducibility and very in-depth knowledge of the target may allow us to go further in the next 10 years.
What changes do you think could improve the professional lives of scientists?
It is always difficult to come and report to well-established scientists that the model they used before was not the best one. It is important that not only the results of a study are discussed but also the limitations of the study, with a clear definition accompanying the paper when it is published. I think this is even a major action to be made when people are overcommunicating on a published paper using social media. We should ensure that everyone is able to balance the results and conclusion of a given study.
What's next for you?
This study is the result of several years of work. It started in 2011 with the genetic characterization of the historical model. It is this first result that is at the origin of this second study. With this improvement, we have reached the end of what we can improve on this model with current techniques. In the future, I want to use this new model for other more fundamental approaches.
Université de Strasbourg, CNRS, INSERM, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Department of Translational Medicine and Neurogenetics, 1 rue Laurent Fries, 67404 Illkirch-Graffenstaden, France.
E-mail: [email protected]
