Download A4. Characterization of the normal and pathophysiological functions

2014 - Doctoral School n° 549
Health, Biological Sciences, & Life Chemistry
Thesis Proposal
1. Thesis Supervisor(s):
Name(s): LAUMONNIER Frédéric
Research Unit : UMR « Imaging and Brain », Inserm U930
Mail: [email protected]
2. Thesis Title : Characterization of the normal and pathophysiological functions of the
synaptic receptor PTCHD1 (Patched Domain Homolog 1) during brain development.
3. Summary :
Autism spectrum disorders (ASD) and intellectual disability (ID) are both major early-onset
neurodevelopmental troubles for which the causes are still undefined and no biomarkers have been
isolated to date. The significant contribution of genetic factors in these disorders allowed to suggest
a probable biological origin, associated with a strong co-morbidity on phenotypic and genetic
aspects. Among the numerous genes identified to date in ASD and ID, most of them are involved in
neuronal and synaptic physiological pathways (e.g. NMDA, AMPA and mGluR5 receptors
complexes) (Laumonnier et al, 2007 ; van Bokhoven et al, 2011) ; Delorme et al, 2013).
Our group has identified a truncating deleterious mutation in the PTCHD1 (Patched Homolog
Domain 1) gene, localized in Xp22.11, in 2 patients from the same family (uncle and nephew) and
with ASD and non syndromic ID. Interestingly, genomic microdeletions involving the PTCHD1
gene locus have been previously described in several ASD patients (Noor et al, 2010), suggesting
that mutations of this gene are strongly linked to ASD and ID.
However, no data regarding the function of PTCHD1, particularly throughout the development of
the central nervous system (CNS) are available. The PTCHD1 gene encodes a predicted
transmembrane protein sharing a secondary structure similar to the Patched receptor. To delineate
the physiological and abnormal function of PTCHD1, we performed several functional analyses
(neurodevelopmental expression profiling, subcellular localization, shRNA study, metabolomics)
on primary neuronal cultures from normal mouse embryonic and adult hippocampus Our
preliminary results suggest that PTCHD1 is a novel synaptic actor régulating neuritogenesis and
synaptogenesis stages.
To understand the consequences, in vivo, of the absence of PTCHD1 on brain development and
functioning, we recently generated the KO mouse model for the Ptchd1 gene through the european
GENCODYS project. The main aim of this thesis project will consist to specifically analyze this
animal model by using complementary approaches in cellular neurobiology allowing to :
. Assess the endogenous expression of the PTCHD1 protein by using custom-made antibodies
. Assess the brain, neuronal and synaptic structures in normal and KO mouse (in embryonic and
postnatal stages)
. Assess the subcellular dynamics and synaptic mobility of PTCHD1, modulated by the activation of
neuronal cells.
In summary, this thesis project will help to better understand the normal role of the PTCHD1 gene
and protein in the CNS, and to provide functional evidence associated with its abnormal expression
in patients with ASD and ID.
References :
(1) Laumonnier F et al. Am J Hum Genet 2007 ; (2) van Bokhoven H. Annu Rev Genet 2011, 45:81-104 ; (3) Delorme
R et al. Nat Med 2013, 19:685-694 ; (4) Noor A et al. Sci Transl Med 2010, 2:49ra68