NeuroGeMM Research Group
Neuro-Genetics and Mouse Models

Head of Research Group: Dr Binnaz YALCIN, PhD, HDR
Email: binnaz.yalcin@inserm.fr
Tel: +33 3 80 39 66 60

Areas of Investigation

Large-scale neuroanatomical profiling of rodent mutants to better understand cognitive disorders

Identification of cellular mechanisms underlying corpus callosum anomalies in WDR genes

Neurobiological studies of Cohen Syndrome disease gene VPS13B in the mouse

Mouse genetic studies at the autism-associated 16p11.2 locus

Large-scale neuroanatomical profiling of rodent mutants to better understand cognitive disorders

We recently published the neuroanatomical characterization of 1,500 mutant mouse lines and identified 198 genes whose disruptions yield NeuroAnatomical Phenotypes (NAPs) in male, mostly affecting structures implicated in brain connectivity including the corpus callosum.

17% of human unique orthologues of mouse NAP genes are known loci for cognitive dysfunction. The remaining 83% constitute a vast pool of genes newly implicated in brain architecture, providing the largest study of mouse NAP genes and gene networks.

The identification of mouse NAP genes and gene networks offers a complementary resource to human genetic studies and predict that many more genes could be involved in mammalian brain morphogenesis and cognition.

Through data-sharing platforms, we are currently reaching out to medical community and ask whether the newly implicated genes we identified in mouse brain development (n=164) are associated with cognitive disorders in humans.

We are also investigating the role of gender specificity in neuroanatomical features by studying males and females independently.

Identification of cellular mechanisms underlying corpus callosum anomalies in WDR genes

One major discovery made by my laboratory was that WDR genes are 3-times more likely to be linked with neuroanatomical defects than any other gene families in particular corpus callosum anomalies. We hypothesize that WDR genes are key regulators of the formation of the corpus callosum, a commissure that provides higher-order neurological advantages in placental mammals. The development of the corpus callosum is a process relying on microtubule polymers that localize to the tip of the axon, known as the growth cone. We chose to focus on WDR47 as a paradigm of WDR function in corpus callosum biology. We showed that in the absence of WDR47, the corpus callosum is absent (a condition known as corpus callosum agenesis) and that WDR47 participates in key microtubule-mediated processes including growth cone dynamics.

Our working model of how growth cone dynamics is altered in the absence of WDR47 is shown below. Our work provides insights showing that WDR47 plays a microtubule stabilizer role in the growth cone. This is supported by the interaction between the N terminus of WDR47 and SCG10 (a very well-known microtubule destabilizer promoting catastrophe at the growth cone), which led us to think that WDR47 might be a regulator of SCG10 activity in the JNK1 pathway. Interestingly, knockout mouse studies of Jnk1 show high behavioral similarities compared with Wdr47. In the absence of WDR47, there is thus increased of microtubule catastrophe at the growth cone. Such defects could be one of the reasons as to why the corpus callosum has not formed.

We are now investigating other WDR-gene mutations implicated in corpus callosum dysgenesis to determine whether common cellular mechanisms may be involved.

Neurobiological studies of Cohen Syndrome disease gene VPS13B

Cohen syndrome is caused by mutations on one single gene: the vacuolar protein sorting 13 homolog B (VPS13B) gene localized on human chromosome eight. Common clinical features include intellectual disability and postnatal microcephaly. VPS13B is a widely-expressed transmembrane protein and based on its homology to the yeast VPS13 protein is thought to function in vesicle-mediated transport and sorting of proteins within the cell.

Our general aim is to improve our knowledge of VPS13B gene function in the brain and pathobiological mechanisms of Cohen syndrome in autosomal recessive intellectual disability as it remains largely unknow.

Mouse genetic studies at the autism-associated 16p11.2 locus

Autism spectrum disorders (ASDs) are a group of complex neurodevelopmental diseases characterized by restricted/repetitive behaviors and a deficit in social communication. Affected children usually express autistic behaviors after  24 months of age. Human locus 16p11.2 is susceptible to a 600 Kb deletion (OMIM #611913) which is among the most frequent known etiologies of ASDs. This 16p11.2 microdeletion arises de novo and associates with brain size and other NeuroAnatomical Phenotypes (NAPs). One of the main challenges in the field is to be able to decipher which could be the causative gene of NAPs at the locus and how the genes could interact with each other to lead to ASDs.

Here we set out to assess the neuroanatomical implication of each individual genes of the 16p11.2 interval using mouse mutants to inform the genetic architecture of this autism-associated locus.