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

Abstract

Neuroinflammation and neurogenesis have both been the subject of intensive investigation over the past 20 years. The sheer complexity of their regulation and their ubiquity in various states of health and disease have sometimes obscured the progress that has been made in unraveling their mechanisms and regulation. A recent study by Kozareva et al. (Neuronal Signaling (2019) 3), provides evidence that the orphan nuclear receptor TLX is central to communication between microglia and neural precursor cells and could help us understand how inflammation, mediated by microglia, influences the development of new neurons in the adult hippocampus. Here, we put recent studies on TLX into the context of what is known about adult neurogenesis and microglial activation in the brain, along with the many hints that these processes must be inter-related.

From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling

“…Herein, our efforts began with the goal of probing conformational space accessible to oleic acid with a panel of designed mimetics and then using a panel of biological assays to inform as to the potency and selectivity profiles of particular ligands within the collection of mimetics prepared. As illustrated in Figure F, it was hoped that these efforts would result in identifying clear differential activities of members of the collection, specifying particular natural-product-inspired mimetics that were selective at GPR40, GPR120, or TLX. ,− Notably, these three receptors are of great interest in biology and medicine: GPR40 (FFAR1) plays a role in incretin release, glucose-dependent insulin secretion, taste, and inflammation and is a therapeutic target for many metabolic diseases, including type 2 diabetes; ,− , GPR120 (FFAR4) regulates fat metabolism and is a therapeutic target for the treatment of obesity; and TLX (NR2E1) is known to modulate adult neurogenesis and is a potential therapeutic target for neurological and psychiatric diseases such as Alzheimer’s, glioblastoma, and schizophrenia. , …”

“…2,4−8 Notably, these three receptors are of great interest in biology and medicine: GPR40 (FFAR1) plays a role in incretin release, glucose-dependent insulin secretion, taste, and inflammation and is a therapeutic target for many metabolic diseases, including type 2 diabetes; 2,4−8,10 GPR120 (FFAR4) regulates fat metabolism and is a therapeutic target for the treatment of obesity; 11 and TLX (NR2E1) is known to modulate adult neurogenesis and is a potential therapeutic target for neurological and psychiatric diseases such as Alzheimer's, glioblastoma, and schizophrenia. 12,13 ■ RESULTS AND DISCUSSION With oleic acid as our target, we contemplated basic features of ligand design and settled on the generic approach depicted in Figure 2A. Basically, retention of the polar carboxylic headgroup and hydrophobic tail ("R") would be followed by strategic installation of chiral conformational constraints differentially positioned about the C 18 acyclic carbon skeleton of the parent fatty acid.…”