Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis
Por:
Kandel, P, Semerci, F, Mishra, R, Choi, W, Bajic, A, Baluya, D, Ma, LH, Chen, K, Cao, AC, Phongmekhin, T, Matinyan, N, Jimenez-Panizo, A, Chamakuri, S, Raji, IO, Chang, L, Fuentes-Prior, P, MacKenzie, KR, Benn, CL, Estebanez-Perpina, E, Venken, K, Moore, DD, Young, DW, Maletic-Savatic, M
Publicada:
29 mar 2022
Resumen:
Neural stem cells, the source of newborn neurons in the adult hippocampus, are intimately involved in learning and memory, mood, and stress response. Despite considerable progress in understanding the biology of neural stem cells and neurogenesis, regulating the neural stem cell population precisely has remained elusive because we have lacked the specific targets to stimulate their proliferation and neurogenesis. The orphan nuclear receptor TLX/NR2E1 governs neural stem and progenitor cell self-renewal and proliferation, but the precise mechanism by which it accomplishes this is not well understood because its endogenous ligand is not known. Here, we identify oleic acid (18:1 omega 9 monounsaturated fatty acid) as such a ligand. We first show that oleic acid is critical for neural stem cell survival. Next, we demonstrate that it binds to TLX to convert it from a transcriptional repressor to a transcriptional activator of cell-cycle and neurogenesis genes, which in turn increases neural stem cell mitotic activity and drives hippocampal neurogenesis in mice. Interestingly, oleic acid-activated TLX strongly up-regulates cell cycle genes while only modestly up-regulating neurogenic genes. We propose a model in which sufficient quantities of this endogenous ligand must bind to TLX to trigger the switch to proliferation and drive the progeny toward neuronal lineage. Oleic acid thus serves as a metabolic regulator of TLX activity that can be used to selectively target neural stem cells, paving the way for future therapeutic manipulations to counteract pathogenic impairments of neurogenesis.
Filiaciones:
Kandel, P:
Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA
Baylor Coll Med, Dept Pharmacol & Chem Biol, Houston, TX 77030 USA
Semerci, F:
Baylor Coll Med, Dept Pediat Neurol, Houston, TX 77030 USA
Texas Childrens Hosp, Jan & Duncan Neurol Res Inst, Houston, TX 77030 USA
Mishra, R:
Baylor Coll Med, Dept Pediat Neurol, Houston, TX 77030 USA
Texas Childrens Hosp, Jan & Duncan Neurol Res Inst, Houston, TX 77030 USA
Choi, W:
Texas Childrens Hosp, Jan & Duncan Neurol Res Inst, Houston, TX 77030 USA
Baylor Coll Med, Med Scientist Training Program, Houston, TX 77030 USA
Tulane Univ, Dept Obstet & Gynecol, New Orleans, LA 70112 USA
Bajic, A:
Texas Childrens Hosp, Jan & Duncan Neurol Res Inst, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA
Baluya, D:
Univ Texas MD Anderson Canc Ctr, Dept Intervent Radiol, Houston, TX 77030 USA
Washington State Univ, Tissue Imaging Metabol & Prote Lab, Pullman, WA 99163 USA
Ma, LH:
Baylor Coll Med, NMR & Drug Metab Adv Technol Cores, Houston, TX 77030 USA
Chen, K:
Rice Univ, Dept Biosci, Houston, TX 77005 USA
Univ Chicago, Pritzker Sch Med, Chicago, IL 60637 USA
Cao, AC:
Rice Univ, Dept Chem, Houston, TX 77005 USA
Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA
Phongmekhin, T:
Rice Univ, Dept Biosci, Houston, TX 77005 USA
Matinyan, N:
Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA
Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA
Jimenez-Panizo, A:
Univ Barcelona, Inst Biomed, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
Chamakuri, S:
Baylor Coll Med, Dept Pharmacol & Chem Biol, Houston, TX 77030 USA
Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
Raji, IO:
Baylor Coll Med, Dept Pharmacol & Chem Biol, Houston, TX 77030 USA
MIT, Koch Inst, Cambridge, MA 02142 USA
Chang, L:
Baylor Coll Med, Dept Pharmacol & Chem Biol, Houston, TX 77030 USA
Fuentes-Prior, P:
Biomed Res Inst St Pau, Mol Basis Dis, Barcelona 08025, Spain
MacKenzie, KR:
Baylor Coll Med, Dept Pharmacol & Chem Biol, Houston, TX 77030 USA
Baylor Coll Med, NMR & Drug Metab Adv Technol Cores, Houston, TX 77030 USA
Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
Benn, CL:
Pfizer Regenerat Med, Cambridge CB21 6GP, England
CSO LoQus23 Therapeut, Cambridge CB22 3AT, England
Estebanez-Perpina, E:
Univ Barcelona, Inst Biomed, Dept Biochem & Mol Biomed, Barcelona 08028, Spain
Venken, K:
Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA
Baylor Coll Med, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA
Moore, DD:
Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA
Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
Young, DW:
Baylor Coll Med, Integrat Mol & Biomed Sci Grad Program, Houston, TX 77030 USA
Baylor Coll Med, Dept Pharmacol & Chem Biol, Houston, TX 77030 USA
Texas Childrens Hosp, Jan & Duncan Neurol Res Inst, Houston, TX 77030 USA
Rice Univ, Dept Chem, Houston, TX 77005 USA
Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
Biomed Res Inst St Pau, Mol Basis Dis, Barcelona 08025, Spain
Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA
Maletic-Savatic, M:
Baylor Coll Med, Dept Pediat Neurol, Houston, TX 77030 USA
Texas Childrens Hosp, Jan & Duncan Neurol Res Inst, Houston, TX 77030 USA
Baylor Coll Med, Ctr Drug Discovery, Houston, TX 77030 USA
Baylor Coll Med, Dept Neurosci, Houston, TX 77030 USA
Green Published, Green
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