Job ID: 106500
PhD project – Towards a potential therapy of a rare form of autism spectrum disorder: Genetic rescue of Tshz3
Position: Ph.D. Student
Deadline: 2 April 2023
Employment Start Date: 2 October 2023
Contract Length: 3 years
Institution: Aix Marseille Université
Department: Marseille Developmental Biology Institute (IBDM),
The NeuroSchool PhD Program of Aix-Marseille University (France) has launched its annual calls for PhD scholarships for students with a master’s degree in a non-French university.
The following project is one of the 14 proposed projects. Not all proposed projects will be funded, check our website for details.
RESEARCH PROJECT :
- State of the art
Autism spectrum disorder (ASD) is characterized by abnormalities in two core behavioral domains, namely deficit in social interactions and restrictive, repetitive patterns of behavior. We identified the gene TSHZ3 as the minimal region of overlap for 19q12 heterozygous deletions in patients with a new syndrome including autistic features and provided evidence, from studies in mouse models, for a link between heterozygous Tshz3 deletion, defects in cortical projection neurons (CPNs), striatal cholinergic interneurons (CINs) and ASD-like deficits. Our data also suggest that the post-natal CamK2-Cre-mediated deletion of Tshz3 leads to ASD behavioral deficits without affecting the viability of the CPNs and CINs1-4. These observations are the ground of this project.
Determine if restoring Tshz3 expression after birth improves ASD-like deficits.
To test this possibility, we generated a conditional rescue mouse model (Tshz3+/STOP) allowing restoring Tshz3 expression following Cre-mediated excision of the STOP cassette inserted in the unique intron of Tshz3 upstream of the exon 2. To restore Tshz3 expression we will use the CamK2-Cre mouse line. In this scheme, Tshz3+/STOP; CamK2-Cre (Tshz3-rescued) embryos will be heterozygous for Tshz3, thus mimicking the condition of TSHZ3 patients with ASD, until after birth when Tshz3 expression will be restored following CamK2-Cre-mediated excision of the STOP cassette. Behavioral testing of Tshz3+/STOP and Tshz3-rescued mice will be performed using a live mouse tracker system (LMT), enabling automatic live tracking, identification and characterization through behavioral labelling of up to four mice in an enriched environment with no time limit. Further characterization of these models will include molecular transcriptomics (scRNAseq) to analyze/compare gene expression in Tshz3+/STOP, Tshz3-rescued and control mice to identify the molecular pathways involved in ASD behavior.
- Expected results
There are no medications currently approved for the treatment of the main core symptom in ASD. This project is a new approach to identify novel treatment options for ASD. Indeed, if Tshz3-associated dysfunctions can be reversed, transcriptomic analysis might identify novel disease genes, including “druggable” differentially expressed genes e.g. encoding a receptor or an enzyme.
Mouse lines and operating LMT are available.
- Expected candidate profile
Master’s degree in biology. Strong interest in neurosciences and mouse behavior. Experience in model organisms; Cell and molecular biology; English writing and speaking; data analysis; team working.