UC Santa Cruz

SATB2-Associated Syndrome (SAS) is a recently described disease characterized by developmental delay, severe intellectual deficiency, and behavioral problems. It is caused by heterozygous de novo mutations in the SATB2 gene, which encodes a DNA-binding protein involved in chromatin remodeling, and often leads to loss-of-function. In the brain, SATB2 expression is mostly restricted to the projection neurons in the cerebral cortex and hippocampus, suggesting the etiology of SAS is likely defects in these neurons. In mice, Satb2 is required for specifying the subtype identities of callosal and subcerebral neurons. In the absence of Satb2, callosal neurons are mis-specified, and the subcerebral neurons are missing. However, prior studies on Satb2 function in brain development were performed using homozygous mutant mice. It remained to be determined how heterozygous loss-of-function of SATB2, as commonly seen in SAS patients, affects brain development.Satb2+/- mice show consistent defects in cortical projection neurons and their axons. Single cell RNA-seq of postnatal day 28 Satb2+/+, Satb2+/-, and Satb2 cko cortices, shows many genes are mis-regulated in the Satb2+/- projection neurons. However, the downstream targets of Satb2 that mediate its functions in cortical neuron development and axon targeting have not been identified. This thesis reviews the function of Satb2 in cortical development and determines mechanisms of Satb2 in organizing higher-order chromatin structure, regulating the development of cortical projection neuron subtypes, and identifies the downstream target genes that mediate the function of Satb2. These findings elucidate fundamental mechanisms of cortical development and illuminate the etiology of SAS, facilitating the development of potential treatment strategies.