Maturation-Promoting Activity of SATB1 in MGE-Derived Cortical Interneurons

Abstract

SummaryThe generation of cortical interneuron subtypes is controlled by genetic programs that are activated in the ventral forebrain and unfold during the prolonged period of inhibitory neuron development. The LIM-homeodomain protein LHX6 is critical for the development of all cortical interneurons originating in the medial ganglionic eminence, but the molecular mechanisms that operate downstream of LHX6 to control the terminal differentiation of somatostatin- and parvalbumin-expressing interneurons within the cortex remain unknown. Here, we provide evidence that the nuclear matrix and genome organizer protein SATB1 is induced by neuronal activity and functions downstream of Lhx6 to control the transition of tangentially migrating immature interneurons into the terminally differentiated Somatostatin (SST)-expressing subtype. Our experiments provide a molecular framework for understanding the genetic and epigenetic mechanisms by which specified but immature cortical interneurons acquire the subtype-defining molecular and morphophysiological characteristics that allow them to integrate and function within cortical circuits.

Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis

“…SATB1 binds to genomic loci of multiple immediate early genes (IEGs) and is required for the proper temporal expression of these genes during postnatal development. SATB1 is also induced by neuronal activity and promotes interneuron maturation (27,28). However, the role of SATB1 in neural stem cell differentiation during embryonic or adult neurogenesis has not been uncovered and our study provides the first evidence for the role of SATB1 in adult neurogenesis.…”

“…S5B), we decided to investigate transcription factors among predicted HuD targets to identify a novel regulatory network between HuD and transcriptional regulators in neural differentiation. Among the transcription factors on the HuD target list, we focused on SATB1 because of its known function in regulating cell linage-specific gene expression during both T-cell development (26) and cortical neuron maturation (27,28). We first assessed the expression of SATB1 and confirmed that it was localized in Nestin +…”

“…SATB1 is well known to orchestrate the temporal and spatial expression of genes during T-cell proliferation and differentiation, thereby ensuring the proper development of this lineage (26,31). SATB1 is differentially expressed in various subsets of neuronal cells and regulates a large number of genes involved in development and differentiation (27,28). Recent studies found that SATB1 is the major SATB family protein in postnatal brains and acts as a ''docking site'' to recruit chromatin modifiers to gene promoters.…”

Lhx6 Directly Regulates Arx and CXCR7 to Determine Cortical Interneuron Fate and Laminar Position

“…In contrast, Arx transduction of Lhx6 mutant MGE cells restored ~25% of the SST cells (Figures 4E′ and 4N′: p = 0.01) and ~80% of the PV cells (Figures 4K′ and 4O′: p = 0.002). Denaxa et al (2012) found that Satb1 is downstream of Lhx6 and promotes SST expression. We also detected loss of Satb1 expression in Lhx6 mutants (Figures S5A–S5F) but Arx transduction did not rescue Satb1 expression in Lhx6 mutants (Figures S5G–S5L).…”

“…However, MGE-derived interneurons from Lhx6 mutants fail to occupy middle neocortical layers and exhibit a preference for superficial and very deep layers (Liodis et al, 2007; Zhao et al, 2008). While Lhx6 promotes the expression of several genes that control cell fate and migration, including Arx, Sox6, CXCR7 (Flandin et al, 2011; Zhao et al, 2008), and Satb1 (Close et al, 2012; Denaxa et al, 2012), only the role of Satb1 in the Lhx6 phenotype has been evaluated.…”