TLX—Its Emerging Role for Neurogenesis in Health and Disease

Abstract

The orphan nuclear receptor TLX, also called NR2E1, is a factor important in the regulation of neural stem cell (NSC) self-renewal, neurogenesis, and maintenance. As a transcription factor, TLX is vital for the expression of genes implicated in neurogenesis, such as DNA replication, cell cycle, adhesion and migration. It acts by way of repressing or activating target genes, as well as controlling protein-protein interactions. Growing evidence suggests that dysregulated TLX acts in the initiation and progression of human disorders of the nervous system. This review describes recent knowledge about TLX expression, structure, targets, and biological functions, relevant to maintaining adult neural stem cells related to both neuropsychiatric conditions and certain nervous system tumours.

Identification of the Wallenda JNKKK as an Alk suppressor reveals increased competitiveness of Alk-expressing cells

“…In addition to its function in terminal patterning in the Drosophila embryo 52 , 79 , tll is expressed in the optic lobe primordium 80 , where it controls cell-fate decisions during Bolwig’s organ and optic lobe precursor development 81 . Interestingly, the mammalian Tll homolog TLX/NR2E1 acts as self-renewal factor in neural stem cells and neuroblastoma tumor spheres, and elevated expression of TLX/NR2E1 is correlated with an unfavorable prognosis in neuroblastoma patients 82 , 83 . We also identified tissue-specific transcription factors, like the PAX6 homolog Eyeless and Eyes absent (EYA) which have been linked to human neuroblastoma 84 , 85 .…”

MYCN -amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling

“…Additionally, the high mRNA levels of the NHR coactivators NCOA1 and NCOA2 also correlated to a favorable NB disease ( Datasets S4 and S5 ) potentially by increasing the activity of NHRs, which may contribute to neural differentiation. Importantly, several human NHRs [e.g., NR1D1 ( 64 ), NR2E1 ( 65 ), NR5A1 ( 66 ), as well as RAR and RXR ( 67 )] are implicated in neurogenesis, maintenance, and a functional neuronal system. The significance of NHRs is further highlighted by the fact that 7 of 18 NHRs are linked to neuronal remodeling in Drosophila melanogaster ( 68 ).…”

The orphan nuclear receptor TLX: an emerging master regulator of cross-talk between microglia and neural precursor cells

“…TLX is expressed in both neurogenic niches (the subventricular zone of the ventricular walls and the subgranular zone of the dentate gyrus), specifically in the neuronal precursor cells (NPCs), which it maintains in a proliferative state by preventing them from undergoing ectopic differentiation. Consistent with this functional role, TLX knockout mice display impaired neurogenic responses, diminished hippocampal volume, impaired long-term potentiation in the dentate gyrus and deficits in hippocampal memory and related behaviors [3][4][5]32,35].…”

“…The orphan nuclear receptor TLX, first identified in retinal photoreceptors 20 years ago [1,2], has been studied mostly for its role in regulating the ongoing creation of new neurons in the adult hippocampus [3][4][5]. This adult neurogenesis occurs in at least several mammalian species, including humans [6][7][8][9][10][11] and has been implicated in learning, memory, stress regulation and maintaining emotional resilience [6,7,[12][13][14].…”