Dissection des fonctions striatales de Foxp1 et Foxp2 dans le comportement social et les comportements habituels
The objectives of the proposal are to study specific and co-regulated functions of the transcription factors (TFs) Foxp1 and Foxp2 in the mouse dorsal and ventral striatum in habit formation and (social) reward respectively. In humans FOXP1 and FOXP2 mutations are associated with autism and developmental speech and language disorders respectively. Since these are arguably more human ‘specific’ disorders, transcriptional targets will be validated in human iPSC derived striatal neurons. We hypothesize that Foxp1 or Foxp2 deficiency share partly overlapping pathomechanisms which might mediate stereotyped behavior and abnormal social interactions.
Behavior of mice carrying conditional Foxp2 gene deletions
Gene expression profiling
Human neurons derived from induced pluripotent stem cells
Set-up new methods in:
Circuit specific gene profiling in-vivo
Differentiation of iPSCs into striatal neurons
The proposal addresses molecular and cellular mechanisms of mental disorders, an urgent public health issue. It aims to deliver functional data which are fundamental to understand susceptible molecular mechanisms and dovetails with current large efforts in genetics to identify risk variants eventually aimed to help prediction and early intervention for mental disorders.
Neurodevelopmental disorders such as speech and language disorders and autism spectrum disorders (ASD) usually show complex inheritance patterns, with multiple genes likely involved. This has brought additional difficulties in investigating and determining the mechanisms underlying these disorders. Genes of the Foxp family (FOXP1 and FOXP2) have been implicated in neurodevelopmental disorders. Mutations and deletions of FOXP1 have been associated with ASD, while mutations and disruptions of FOXP2 cause a severe neurodevelopmental speech and language disorder. The identification of these single genes of the same family associated with these disorders provides an important entry point to investigate the molecular and circuit mechanisms underlying these disorders. Interestingly, Foxp1 and Foxp2 have been shown to interact in vitro. Furthermore, FOXP2 has been shown to directly down-regulate transcription of genes that have been implicated in ASD. These studies indicate that although FOXP1 and FOXP2 related disorders have distinct endophenotypes, the underlying molecular mechanisms may overlap. Interestingly, Foxp1 and Foxp2 are highly co-expressed in medium spiny neurons of the striatum, a brain region that has been implicated in the learning of precise motor sequences and in speech and social behavior. This is relevant because some of the most important endophenotypes observed in these disorders are related to altered automatisation of sequences or repetitive motor patterns and altered social interactions. Therefore, we propose to investigate the striatal roles of Foxp1 and Foxp2 in automatisation of movement and in social behaviour. Furthermore, we will determine if they interact functionally in vivo by genetic epistasis and transcriptional analyses. Finally, we will investigate the alterations in neural activity and molecular networks associated with Foxp1 and Foxp2 related dysfunction. These experiments will shed new light into the etiology of neurodevelopmental disorders and will explore the possibility that many of these disorders share common origins at the molecular and circuit levels.
Monsieur Matthias GROSZER (Institut du Fer à Moulin, Inserm UPMC)
L'auteur de ce résumé est le coordinateur du projet, qui est responsable du contenu de ce résumé. L'ANR décline par conséquent toute responsabilité quant à son contenu.
UMR-S839 Institut du Fer à Moulin, Inserm UPMC
Champlimaud Institute Champlimaud Institute Lisbonne Portugal
Aide de l'ANR 195 624 euros
Début et durée du projet scientifique : février 2014 - 36 Mois