Abstract
Satb2-associated syndrome (SAS) is a genetic disorder that results from the deletion or mutation of one allele within the Satb2 locus. Patients with SAS show behavioral abnormalities, including developmental delay/intellectual disability, hyperactivity, and symptoms of autism. To address the role of Satb2 in SAS-related behaviors and generate an SAS mouse model, Satb2 was deleted in the cortex and hippocampus of Emx1-Cre; Satb2flox/flox [Satb2 conditional knockout (CKO)] mice. Satb2 CKO mice showed hyperactivity, increased impulsivity, abnormal social novelty, and impaired spatial learning and memory. Furthermore, we also found that the development of neurons in cortical layer IV was defective in Satb2 CKO mice, as shown by the loss of layer-specific gene expression and abnormal thalamocortical projections. In summary, the abnormal behaviors revealed in Satb2 CKO mice may reflect the SAS symptoms associated with Satb2 mutation in human patients, possibly due to defective development of cortical neurons in multiple layers including alterations of their inputs/outputs.
Highlights
Special AT-rich sequence-binding protein 2 (Satb2) is a transcription factor that regulates chromatin remodeling and gene expression via interactions with genomic nuclear matrix attachment regions, and it plays a pivotal role in the development of multiple organs
Unlike conventional Satb2 mutant mice, which died at birth (Alcamo et al, 2008; Britanova et al, 2008), all the Satb2 conditional knockout (CKO) mice survived after birth and about 2/3 of CKO mice survived into adulthood (Figures 1E,F)
It is clear that Satb2 deletion in the cerebral cortex and hippocampus leads to growth retardation, which is present in patients with Satb2-associated syndrome (SAS) (Zarate and Fish, 2017)
Summary
Special AT-rich sequence-binding protein 2 (Satb2) is a transcription factor that regulates chromatin remodeling and gene expression via interactions with genomic nuclear matrix attachment regions, and it plays a pivotal role in the development of multiple organs. Satb is essential for the craniofacial patterning and bone formation (Dobreva et al, 2006). Satb is required for the development of both callosal and subcortical projection neurons in the neocortex (Alcamo et al, 2008; Britanova et al, 2008; Leone et al, 2015; McKenna et al, 2015). In Satb conventional knockout mice and Satb CKO mice, most of callosal neurons do not send axons to the contralateral cortex (Alcamo et al, 2008; Leone et al, 2015). Patients with SAS show craniofacial anomia, growth retardation, and behavioral abnormalities such as developmental delay/intellectual disability, hyperactivity, and symptoms of autism (Usui et al, 2013; Zarate and Fish, 2017; Zarate et al, 2018)
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