Satb2 Regulates the Differentiation of Both Callosal and Subcerebral Projection Neurons in the Developing Cerebral Cortex

Abstract

The chromatin-remodeling protein Satb2 plays a role in the generation of distinct subtypes of neocortical pyramidal neurons. Previous studies have shown that Satb2 is required for normal development of callosal projection neurons (CPNs), which fail to extend axons callosally in the absence of Satb2 and instead project subcortically. Here we conditionally delete Satb2 from the developing neocortex and find that neurons in the upper layers adopt some electrophysiological properties characteristic of deep layer neurons, but projections from the superficial layers do not contribute to the aberrant subcortical projections seen in Satb2 mutants. Instead, axons from deep layer CPNs descend subcortically in the absence of Satb2. These data demonstrate distinct developmental roles of Satb2 in regulating the fates of upper and deep layer neurons. Unexpectedly, Satb2 mutant brains also display changes in gene expression by subcerebral projection neurons (SCPNs), accompanied by a failure of corticospinal tract (CST) formation. Altering the timing of Satb2 ablation reveals that SCPNs require an early expression of Satb2 for differentiation and extension of the CST, suggesting that early transient expression of Satb2 in these cells plays an essential role in development. Collectively these data show that Satb2 is required by both CPNs and SCPNs for proper differentiation and axon pathfinding.

TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons

“…We performed a novel analysis of the original spatio-temporal human brain transcriptome data set, using TSHZ3 as a seed, to identify the 49 genes whose expression profiles show the highest correlation with TSHZ3 in the developing neocortex. This TSHZ3 network contains 34 ASD candidate genes, out of which 6 encode transcription factors that are key regulators of CPN identity and connectivity: TBR1 16,17 , FEZF2 14,18 , FOXG1 13 , SATB2 19,21 , SOX5 31,32 and MEF2C 33,34 ( Supplementary Fig. 1a,b and Supplementary Table 1 ).…”

Mutual regulation between Satb2 and Fezf2 promotes subcerebral projection neuron identity in the developing cerebral cortex

“…Previous studies showed that callosal and subcerebral axons failed to reach their targets in the Satb2 mutant mice (16)(17)(18)25). To investigate the molecular underpinning of these defects, we performed gene expression analysis of Satb2 lacZ/lacZ cortices by using RNA sequencing (RNA-seq).…”

“…Previous studies using mouse models revealed that SATB2 was essential for specifying callosal neuronal fate by repressing subcerebral identity in these cells (17)(18)(19)24). Intriguingly, a recent paper reported that SATB2 is also required for the development of subcerebral axons (25). However, it remains unknown how SATB2 performs two seemingly opposing functions.…”

Satb2 Is Required for the Development of a Spinal Exteroceptive Microcircuit that Modulates Limb Position

“…Satb2 is a DNA binding protein that interacts with nuclear matrix attachment regions and controls gene expression and chromatin remodeling. Functional studies of Satb2 have identified roles for this gene in musculoskeletal development, and shown this factor is necessary for establishing the proper identity and axon projections of callosal neurons (Alcamo et al, 2008; Britanova et al, 2008; Dobreva et al, 2006; Leone et al, 2014; Zhao et al, 2014). Interestingly, case studies of human mutations in the Satb2 gene have reported developmental delays in motor skill acquisition, coordination, and sensorimotor behavior (Balasubramanian et al, 2011; FitzPatrick et al, 2003; Van Buggenhout et al, 2005).…”