Role of Negr1 signaling dysregulation in Fragile X and other rare syndromic forms of autism.

Autism spectrum disorders (ASDs) are a group of medical conditions with different causes, which originate early in life. Despite the fact that hundreds of diverse gene mutations can cause ASDs, all of them present common core symptoms (i.e., social/communication deficits, repetitive behavior). Finding common molecular mechanisms disrupted in diverse forms ASDs may explain how the wide variety of ASD genetic variants eventually converge into a consistent core group of impaired behaviors. In this project, we will investigate the hypothesis that the protein Negr1 together with its typical interacting-partner FGFR2 form a central hub commonly de-regulated in diverse ASD mouse models. Indeed, literature data and our preliminary results indicate Negr1 excessive expression in people with autism or Fragile X (ASD leading genetic cause) and in five diverse mouse models of genetic ASDs (including Fragile X). Here, we will investigate if and how acting on Negr1-FGFR2 complex may rescue brain development and ASD behavioral phenotypes in Fragile X mice (as an example for the other ASDs), and whether Negr1-FGFR2 complex is dysregulated also in other further seven mouse models of rare neurodevelopmental disorders with comorbidities in the autism spectrum (e.g., Rett Syndrome) and non-genetic models of ASD (e.g., prenatal-valproic-acid-exposure). Altogether, our project will assess whether and how the Negr1-FGFR2 complex is a central hub for diverse forms of ASD in mice, paving the way to new therapeutic approaches, and possibly drug-repurposing/discovery or gene-therapy programs common to numerous other ASDs.