Satb2 gene dosage in cortical projection neurons impacts neuronal maturation and somatosensory processing [CUT&RUN]

SATB2 Associated Syndrome (SAS) is characterized by severe intellectual deficiency (ID) with limited or absence of speech, behavioral problems, and craniofacial abnormalities. It is caused by de novo heterozygote mutations in the Special AT-rich sequence-Binding Protein 2 (SATB2) gene, which encodes a DNA-binding protein involved in chromatin remodeling. In the brain, SATB2 expression is mostly restricted to the projection neurons in the cerebral cortex and hippocampus. Much of what is known about SATB2 function in brain development comes from studies using homozygous loss-of-function mutant mice. Nonetheless, the heterozygous loss of SATB2 negatively impacts brain development, as identified in SAS patients. Here, we report a dose-dependent requirement for Satb2 in regulating subtype specification for layer 5 subcerebral and all intra-telencephalic neurons, as a modulator of gene expression, through its binding to gene promoters and enhancers of many ID genes. Consequently, Satb2 haploinsufficiency in humans, and in mice as we show here, results in aberrations of cortical projection axons that impact mouse sensory behavior including discriminative touch and vocalization. Our findings uncover fundamental mechanisms underlying the etiology of SAS.