The nuclear receptor tailless induces long-term neural stem cell expansion and brain tumor initiation

Abstract

Malignant gliomas are the most common primary brain tumors, and are associated with frequent resistance to therapy as well as poor prognosis. Here we demonstrate that the nuclear receptor tailless (Tlx), which in the adult is expressed exclusively in astrocyte-like B cells of the subventricular zone, acts as a key regulator of neural stem cell (NSC) expansion and brain tumor initiation from NSCs. Overexpression of Tlx antagonizes age-dependent exhaustion of NSCs in mice and leads to migration of stem/progenitor cells from their natural niche. The increase of NSCs persists with age, and leads to efficient production of newborn neurons in aged brain tissues. These cells initiate the development of glioma-like lesions and gliomas. Glioma development is accelerated upon loss of the tumor suppressor p53. Tlx-induced NSC expansion and gliomagenesis are associated with increased angiogenesis, which allows for the migration and maintenance of brain tumor stem cells in the perivascular niche. We also demonstrate that Tlx transcripts are overexpressed in human primary glioblastomas in which Tlx expression is restricted to a subpopulation of nestin-positive perivascular tumor cells. Our study clearly demonstrates how NSCs contribute to brain tumorgenesis driven by a stem cell-specific transcription factor, thus providing novel insights into the histogenesis and molecular pathogenesis of primary brain tumors.

CBX7 and miR‐9 are part of an autoregulatory loop controlling p16INK4a

“…Some of these targets can potentially explain the physiological effects of miR‐9. For example, the ability of miR‐9 to inhibit cell proliferation has been linked to downregulation of MTHFD2 expression in cancer cells (Selcuklu et al ., 2012) or TLX/NR2E1 in neural stem cells (Liu et al ., 2010; Zhu et al ., 2014). The regulation of CXCR4 by miR‐9 has also been invoked to explain the effect of miR‐9 on cell growth (Yu et al ., 2013).…”

“…Several miR‐9 target genes have been described that might play a role in this context. One of the most prominent is the nuclear receptor NR2E1 (also called TLX), which is essential for the proliferation and self‐renewal of neural stem cells (NSC) and brain tumour stem cells (BTSC) (Liu et al ., 2010; Zhu et al ., 2014). Besides its role in the brain, miR‐9 also influences normal physiology and tumour development in other tissues.…”

Epigenetic regulation of aging stem cells

“…In cultured neurospheres, TLX complexes with and recruits these modifiers to the promoters of the antiproliferative genes p21 CIP1 and Pten, thereby reducing histone acetylation and methylation levels and promoting NSC proliferation (Sun et al, 2007(Sun et al, , 2010. Adult NSCs overexpressing Tlx in vivo show enhanced expression of Bmi1 (Liu et al, 2010), suggesting that TLX may also impact chromatin state by altering expression of additional chromatin modifiers. Whether TLX is deregulated during aging is not yet known, but overexpression of Tlx in SVZ NSCs reduces the decline in stem cell proliferation in old mice (Liu et al, 2010).…”

“…Adult NSCs overexpressing Tlx in vivo show enhanced expression of Bmi1 (Liu et al, 2010), suggesting that TLX may also impact chromatin state by altering expression of additional chromatin modifiers. Whether TLX is deregulated during aging is not yet known, but overexpression of Tlx in SVZ NSCs reduces the decline in stem cell proliferation in old mice (Liu et al, 2010). Although TLX is believed to be mostly a cell-intrinsic regulator, this transcription factor may integrate environmental signals to regulate chromatin states and stem cell function during aging.…”

The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases

“…Given the validated function of TLX in neural stem cells (NSCs) and brain development, it has been suggested that defects in TLX are associated with several human mental illnesses such as schizophrenia and bipolar disorders [15]. TLX has also been associated with NSC expansion and brain tumorigenesis [16].…”