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Retinal Anomalies In Mouse Models With Altered Dosage Of Mouse Orthologs Of The Genes Of Human Chromosome 21

Reference : PhD Yann HERAULT

Offer publication : April 5, 2016

The DYRK1A gene (Dual specificity tyrosine(Y) Regulated Kinase 1A), present on human chromosome 21 (HSA21), codes for a kinase with multiple substrates in various signaling pathways. This gene is expressed in the brain and retina during development and in adulthood. Located in the “Down Syndrome Critical Region”, it is one of the gens which triplication affects most the cognitive functions in T21. Its haplo-insufficiency also
leads to a syndrome with severe ID associated with microcephaly, epilepsy and autistic traits. In mice, both haplo-insufficiency and increased gene dosage of Dyrk1a lead to deficits in cognitive tests, respectively associated with microcephaly and inner retina thinning, or macrocephaly and inner retina thickening. Many recent studies suggest that increased production of DYRK1A is the cause of synaptic transmission deficits and overproduction
of GABA in the brain of murine models of T21. The inner retina anomalies have been attributed to the control of caspase 9 activity by DYRK1A, but the impact on the various retinal neuron populations, and on the visual processing, haven’t been characterized.

This thesis project aims at using the retina, a well-structured part of the Central Nervous System, to better understand both the retinal and brain anomalies induced by changes in expression of Dyrk1a, and the impact of interactions between Dyrk1a and other genes of HSA21. Our preliminary data suggest that most of the inner retina thickness changes are attributable to GABAergic interneurons. By combining immunohistochemistry and in
situ hybridization, we will determine which subpopulations are the most affected, and at which developmental step is concerned. The corresponding interneuron subpopulations in the hippocampus and cortex will be characterized by immunohistochemistry and electrophysiology, to better understand the impact on brain function, particularly in the susceptibility to epilepsy caused by Dyrk1a haplo-insufficiency. Function and/or expression of DYRK1A being modulated by other genes of HSA21, we will use the same strategy on murine models presenting a trisomy or monosomy of segments orthologs
to various regions of HSA21. In those models, we will also analyze the corneal structure, to identify the gene(s) implicated in the formation of keratoconus.

- WISHED SKILLS : The candidate must hold a Master degree in biology and have previously worked in a research laboratory. Knowledge inneurobiology, imaging and eventually electrophysiology are required. He or she should be motivated, rigorous, able to work in a team, and progress quickly toward independence. Finally, he or she should be able to communicate (oral/writing) in both French and English.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The candidate will learn basic techniques in immunohistochemistry, in situhybridization, confocal (and possibly electronic) microscopy, electrophysiology on acute brain slices, in vivo retinal imaging (Optical Coherence Tomography, fundus imaging), and to manage mouse colonies (breeding, genotyping).

Your application

Application Deadline : Dec. 31, 2016

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