TLX: A master regulator for neural stem cell maintenance and neurogenesis

Abstract

The orphan nuclear receptor TLX, also known as NR2E1, is an essential regulator of neural stem cell (NSC) self-renewal, maintenance, and neurogenesis. In vertebrates, TLX is specifically localized to the neurogenic regions of the forebrain and retina throughout development and adulthood. TLX regulates the expression of genes involved in multiple pathways, such as the cell cycle, DNA replication, and cell adhesion. These roles are primarily performed through the transcriptional repression or activation of downstream target genes. Emerging evidence suggests the misregulation of TLX might play a role in the onset and progression of human neurological disorders making this factor an ideal therapeutic target. Here, we review the current understanding of TLX function, expression, regulation, and activity significant to NSC maintenance, adult neurogenesis, and brain plasticity.

Structural basis for corepressor assembly by the orphan nuclear receptor TLX

“…In adult mouse brains, TLX functions as a transcriptional repressor that is critical for the regulation of neurogenesis and the progression of neural stem cell-dependent gliomagenesis (Sun et al 2007;Liu et al 2008Liu et al , 2010Zou et al 2012). Thus, TLX has been suggested as a therapeutic target for the treatment of human neurological disorders and brain tumors (Islam and Zhang 2014), and a recent study showed that TLX activity can be regulated by small molecules (Benod et al 2014). These exciting findings suggest that our crystal structures of TLX may also provide a rational template to develop drugs for the treatment of TLX-related diseases.…”

“…Both TLX and Atrophin are conserved proteins that play important physiological roles in mammals and insects (Gui et al 2011;Islam and Zhang 2014). In adult mouse brains, TLX functions as a transcriptional repressor that is critical for the regulation of neurogenesis and the progression of neural stem cell-dependent gliomagenesis (Sun et al 2007;Liu et al 2008Liu et al , 2010Zou et al 2012).…”

“…As a result, dTLX restricts gap gene expression within the trunk region, thus allowing the terminal cell fates to be specified (Pignoni et al 1990;Steingrimsson et al 1991;YounossiHartenstein et al 1997). In mice, TLX governs eye development and neurogenesis (Shi et al 2004;Zhang et al 2006Zhang et al , 2008Islam and Zhang 2014). TLX also promotes neural stem cell self-renewal by down-regulating the expression of cell cycle check genes such as PTEN and p21 (Zhang et al 2006;Sun et al 2007).…”

Conserved and Exapted Functions of Nuclear Receptors in Animal Development

“…A variety of retinopathies also result from Tlx mutation, indicating that it plays a critical role in the development and maintenance of retinal cells [162]. Tlx plays a role in neural stem cell self-renewal and adult neurogenesis [163], where it functions upstream of a Wnt signaling pathway [164]. In mutant Tlx mice, neural stem cells undergo precocious maturation to neurons and are therefore quickly depleted, resulting in mice with smaller gyrus and forebrain regions [165,166].…”

Steroid Hormones and the Physiological Regulation of Tissue-Resident Stem Cells: Lessons from the Drosophila Ovary

“…For example, Beyaz and colleagues identified peroxisome proliferator-activated receptor-δ (PPAR-δ) and its heterodimeric binding partners liver/retinoid X receptor (LXR/RXR) as mediators of fatty acid-induced enhancement of intestinal stem cell proliferation and self-renewal, despite evidence that PPAR-δ is dispensable for normal intestinal stem cell function [62]. Another example is the nuclear receptor Tailless (TLX), which is directly required for the maintenance and proliferation of mammalian neural stem cells [63]. Gene knockout approaches in mammals for other nuclear hormone receptors, such as the Retinoic Acid Receptor, have yielded mixed results, possibly due to considerable functional redundancy between receptors [64].…”