Satb1 Is an Activity-Modulated Transcription Factor Required for the Terminal Differentiation and Connectivity of Medial Ganglionic Eminence-Derived Cortical Interneurons

Abstract

Although previous work identified transcription factors crucial for the specification and migration of parvalbumin (PV) and somatostatin (SST)-expressing interneurons, the intrinsic factors required for the terminal differentiation, connectivity and survival of these cell types remain uncharacterized. Here we demonstrate that, within subpopulations of cortical interneurons, the special AT-rich binding protein (Satb1) functions in this capacity. We find that conditional removal of Satb1 in mouse interneurons results in the loss of a majority of SST-expressing cells across all cortical layers, as well as some PV-expressing cells in layers IV and VI, by postnatal day 21. SST-expressing cells initially migrate to the cortex in Satb1 mutant mice, but receive reduced levels of afferent input and begin to die during the first postnatal week. Electrophysiological characterization indicates that loss of Satb1 function in interneurons results in a loss of functional inhibition of excitatory principal cells. These data suggest that Satb1 is required for MGE-derived interneuron differentiation, connectivity and survival.

Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes 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 +…”

Single-Cell Profiling of an In Vitro Model of Human Interneuron Development Reveals Temporal Dynamics of Cell Type Production and Maturation

“…It is also possible that some interneuron subtypes require excitatory input for survival and maturation, rendering monocultures suboptimal for survival and function of GABAergic neurons (Close et al, 2012;De Marco Garcia et al, 2011). These factors must be taken into account, as a clear understanding of the molecular mechanisms of subtype specification relies on the ability to produce these cells in the first place.…”

“…PHLDA1 was identified as a downstream target of aristalless (ARX), which is itself crucial for interneuron development and migration (Friocourt and Parnavelas, 2011). A specific role for these genes in SST cells will require careful genetic dissection, as past work has shown that genes expressed in multiple subtypes do not necessarily perform similar functions at equivalent stages of maturation, and may depend on combinations of factors within each subtype as they diverge (Batista-Brito et al, 2009;Close et al, 2012). Their precise role will likely need to be determined in a nonhuman model in order to uncover any specific effects of deletion or overexpression in SSTexpressing interneurons.…”

Development of Cortical Interneurons

“…Downstream of Nkx2.1, Lhx6, a direct target of Nkx2.1 , is expressed permanently in most MGE-derived LCNs from around the time of cell cycle exit (Lavdas et al, 1999;Liodis et al, 2007). Little is known about the transcriptional cascades leading to terminal maturation of cortical LCNs in the postnatal cortex, although Sox6 appears to be an important effector of Lhx6 signaling (Azim et al, 2009;, and Satb1 also has a role downstream of Lhx6 (Close et al, 2012).…”

“…In the first stage, LCN attains their mature fates, defined by their distinctive connectivities, neurochemistries, and firing properties, which culminate in their attaining distinct functions within juvenile cortical circuits (Ascoli et al, 2008). A detailed discussion of this process is beyond the scope of this review, but interacting influences of transcription factors (Close et al, 2012;Cobos et al, 2005), neurotransmitters (Eggan et al, 2012), neurotrophins (Huang et al, 1999), cell adhesion molecules (Pillai-Nair et al, 2005), and their activities are clearly in play (Bartolini et al, 2013;Batista-Brito and Fishell, 2009). The second stage of LCN maturation occurs in concert with cortical circuitry maturation, a process that begins in the early postnatal time period but is not finally achieved in all cortical regions until adolescence or young adulthood.…”