Impact of SHH on CNTNAP2, a gene linked to Autism Spectrum Disorder, during brain development – CASHH

The CASHH project aims to characterize the genetic and functional interaction between two genes, CNTNAP2 and SHH, associated with neurodevelopmental disorders (NDDs), respectively autism spectrum disorders (ASD) and holoprosencephaly (HPE). NDDs have complex etiologies, and the genetic alterations identified in patients do not by themselves explain the development of these pathologies. This underscores the critical need to study the common genetic and signaling programs that may interact in NDDs. CNTNAP2, a major risk gene for ASD, encodes a transmembrane protein important for neuronal myelination and synapse formation. Our preliminary results suggest that CNTNAP2 is repressed by SHH, a morphogen essential for nervous system formation. This raises important questions about the mechanisms and implications of this regulation. The interest of this project, in addition to exploring a novel regulatory pathway by SHH, lies in its potential to elucidate the mechanisms regulating CNTNAP2 expression during normal and pathological brain development. We will use a multidisciplinary approach including in vivo manipulations (transgenic mice), in vitro experiments (iPSC-derived brain organoids from ASD and HPE patients), and genetic and epigenetic analyses to elucidate how SHH regulates CNTNAP2 during cortical development. Transcriptomic and epigenomic analyses of iPSCs will also help identify the regulatory pathways disrupted in NDDs. The partners involved, who have unique expertise in SHH signaling, CNTNAP2, gene expression control and NDDs, will each bring complementary perspectives. Ultimately, this project will have an impact in several biomedical fields such as neuronal development and epigenetics, as well as in patient care.