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Specification Of The Role Of Dyrk1a In The Development Of The Gabaergic Inhibitory And Glutamatergic Excitatory Systems

Reference : PhD Véronique BRAULT

Offer publication : April 5, 2016

Dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is a serine-threonine protein kinase with multiple substrates involved in several cellular mechanisms including neurogenesis, proliferation, differentiation, synapse plasticity and apoptosis. DYRK1A gene appears to be an important gene in intellectual disabilities as it lies in the Down Syndrome (DS ou Trisomy 21, T21) critical region on the human chromosome
21 and its heterozygous mutation in human causes a severe intellectual disability syndrome with microcephaly, epilepsy and autistic traits (MRD7, MIM614104). In mice, Dyrk1a overexpression resulted in slight increase of brain size, a disequilibrium in the excitation/inhibition balance toward
inhibition, a resistance to epilepsy induced by injection of a proconvulsant agent PTZ and alteration of learning and memory abilities. On the other hand, Dyrk1a heterozygous mice presented with microcephaly, increased density of excitatory neurons leading to a disequilibrium in the excitatory/inhibitory balance toward excitation, increase susceptibility to seizures induced by PTZ injection, developmental delay and learning and
behavioral defects. Altogether these data suggest that Dyrk1a gene dosage impacts cognitive functions and neuronal development with differential impact on excitatory and inhibitory neurons.

The aim of the thesis project is to investigate the role of Dyrk1a in neuronal development by analyzing separately its role in the development of the inhibitory system and in the development of the excitatory system. Several mouse lines are available in the laboratory for this project: the Dyrk1a <KO> mouse line (Dyrk1a-/+) and the conditional Dyrk1a mouse line, Dyrk1a <cKO>, allowing a conditional deletion of the Dyrk1a mouse gene. This mouse line will be cross with either the Tg(Dlx6a-cre)1Mekk line that express the Cre recombinase from embryonic day 10 in the GABAergic post-mitotic interneurons (Dyrk1aDlx6a-cre/wt) or with the Tg(Emx1-Cre) line that express the Cre recombinase from embryonic day 10 in the glutamatergic neuron progenitors (Dyrk1aEmx1-cre/wt). We will determine the consequences of the deletion of Dyrk1a gene on neuronal development by analyzing the effects on proliferation of excitatory and inhibitory neuronal precursor cells, migration of post-mitotic neurons and their differentiation in the cortex, striatum and hippocampus from Dyrk1a-/+, Dyrk1aDlx6a-cre/wt and Dyrk1aEmx1-cre/wt mice. Neuronal precursor proliferation will be studied at different embryonic stages by counting excitatory and inhibitory precursors by immunohistochemistry with specific markers. Neuronal migration will be realized at different embryonic stages by looking at neuronal distribution in the cortex, striatum and hippocampus and at the leading
edge of migrating neurons in the le cortex. The study of neuronal differentiation will be performed at different post-natal stages and in adult by:

1) counting the different neuronal sub-populations to determine which sub-population may be affected or not,

2) morphological analysis of excitatory glutamatergic and inhibitory GABAergic neurons and

3) electrophysiological analysis to determine the functional consequences of Dyrk1a deletion in excitatory glutamatergic and inhibitory GABAergic neurons. In addition, we will perform transcriptome analysis at the different embryonic stages analyzed (proliferation, migration and differentiation) for the different mouse line to identify the different molecular pathways involved. The comparison of all mouse lines, Dyrk1a-/+, Dyrk1adlx6a-cre/wt and Dyrk1aEmx1-cre/wt will allow to attribute the Dyrk1a-/+ phenotypes to either inhibitory
GABAergic and/or glutamatergic excitatory systems.

- WISHED SKILLS : The candidate must hold a Master degree in biology with previous research laboratory experience. Background in neurosciences, development, molecular biology and eventually genetics are required. He or she should be enthusiastic, motivated, rigorous and able to work in a team
and to acquire independence. Finally, he or she should have good oral expression and writing capacities in both French and English.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The candidate will learn basic techniques in mouse genetics and phenotyping (maintenance of colonies, genotyping, physiological analyses), in histology (embryos dissection, paraffin and cryosections, immunohistochemistry, classical and confoncal microscopy), in molecular biology (DNA, RNA and protein extraction and analysis) and cell biology. He or she will also benefit from a training in new techniques of genomic and transcriptional analyses (transcriptome and RNAseq) and will have the occasion to collaborate with French and European partners.

Your application

Application Deadline : Dec. 31, 2016

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