Cortex-specific Tmem169 Deficiency Induces Defects in Cortical Neuron Development and Autism-like Behaviors in Mice

The development of the nervous system is a complex process, with many challenging scientific questions yet to be resolved. Disruptions in brain development are strongly associated with neurodevelopmental disorders, such as intellectual disability and autism. While the genetic basis of autism is well established, the precise pathological mechanisms remain unclear. Variations on chromosome 2q have been linked to autism, yet the specific genes responsible for the disorder have not been identified. This study investigates the role of the transmembrane protein 169 (Tmem169) gene, located on human chromosome 2q35, which has not been previously characterized. Our findings indicate that Tmem169 is highly expressed in the nervous system, and its deletion in the male mouse dorsal forebrain results in neuronal morphological abnormalities and synaptic dysfunction. Notably, Tmem169-deficient mice, irrespective of sex, display behavioral traits resembling those observed in individuals with autism. These results suggest that Tmem169 interacts with several key neuronal proteins, many of which are implicated in neurodevelopmental diseases. Furthermore, we demonstrate that Tmem169 promotes neuronal process and synapse development through its interaction with Shank3. Significance statement The prevalence of autism worldwide is estimated to be around 1-2%, causing significant burdens for both patients and their families. Our research reveals that Tmem169 not only interacts with important protein products of genes associated with autism, but also influences the levels of many critical synaptic proteins at synapses. We also demonstrated Tmem169 modulates neuronal process and synapse development at least partially via Shank3. Specific knockout of the Tmem169 gene in the cortex of mice induce autism-like behaviors. These findings provide the first insight into the role of the Tmem169 gene in neurodevelopment and offer new avenues for potential treatments and serve as an important theoretical basis for early screening and enhancing population quality related to autism.