TLX3 regulates CGN progenitor proliferation during cerebellum development and its dysfunction can lead to autism

<i>Tlx3</i>, a master regulator of the fate specification of excitatory neurons, is primarily known to function in post-mitotic cells. Although we have previously identified TLX3 expression in the proliferating granule neuron progenitors (GNPs) of cerebellum, its primary role is unknown. Here, we demonstrate that the dysfunction of <i>Tlx3</i> from the GNPs significantly reduced its proliferation through regulating anti-proliferative genes. Consequently, the altered generation of GNPs resulted in cerebellar hypoplasia, patterning defects, granule neuron-Purkinje ratio imbalance, and aberrant synaptic connections in the cerebellum. This altered cerebellar homeostasis manifested into a typical autism-like behavior in mice with motor, and social function disabilities. We also show the presence of <i>TLX3</i> variants with uncharacterized mutations in human cases of autism spectrum disorder (ASD). Altogether, our study establishes <i>Tlx3</i> as a critical gene involved in developing GNPs and that its deletion from the early developmental stage culminates in autism.