Oleic acid is an endogenous ligand of TLX/NR2E1 that triggers hippocampal neurogenesis
Kandel, Prasanna (Department of Biochemistry and Molecular Biomedicine. Institute of Biomedicine. University of Barcelona)
Semerci, Fatih (Universitat de Barcelona. Institut de Biomedicina)
Mishra, Rachana (Jan and Dan Duncan Neurological Research Institute. Texas Children's Hospital)
Choi, Willian (Medical Scientist Training Program. Baylor College of Medicine)
Bajic, Aleksandar (Department of Molecular and Human Genetics. Baylor College of Medicine)
Baluya, Dodge (Department of Interventional Radiology. University of Texas MD Anderson Cancer Center)
Ma, Li Hua (NMR and Drug Metabolism Advanced Technology Cores. Baylor College of Medicine)
Chen, Kevin (Department of Biosciences. Rice University)
Cao, Austin C. (Department of Chemistry. Rice University)
Phongmekhin, Tipwarin (Department of Biosciences. Rice University)
Matinyan, Nick (Verna and Marrs McLean Department of Biochemistry and Molecular Biology. Baylor College of Medicine)
Jimenez-Panizo, Alba (Universitat de Barcelona. Institut de Biomedicina)
Chamakuri, Srinivas (Department of Pathology and Immunology. Baylor College of Medicine)
Raji, Idris O. (Department of Pharmacology & Chemical Biology. Baylor College of Medicine)
Chang, Lyra (Department of Pharmacology & Chemical Biology. Baylor College of Medicine)
Fuentes-Prior, Pablo (Institut d'Investigació Biomèdica Sant Pau)
MacKenzie, Kevin R. (Department of Molecular and Cellular Biology. Baylor College of Medicine)
Benn, Caroline L. (Pfizer Regenerative Medicine)
Estebanez-Perpiña, Eva (Department of Biochemistry and Molecular Biomedicine. Institute of Biomedicine. University of Barcelona)
Venken, Koen (Verna and Marrs McLean Department of Biochemistry and Molecular Biology. Baylor College of Medicine)
Moore, David D. (Department of Molecular and Cellular Biology. Baylor College of Medicine)
Young, Damian W. (Center for Drug Discovery. Baylor College of Medicine)
Maletic-Savatic, Mirjana (Department of Neuroscience. Baylor College of Medicine)

Data:	2022
Resum:	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 (18:1ω9 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.
Nota:	Altres ajuts: Cancer Prevention and Research Institute of Texas (CPRIT), Core Facility Support Award (CPRIT-RP180672, R1313, 1R01GM138781-01); NIH (CA125123, RR024574); Eunice Kennedy Shriver National Institute of Child Health & Human Development of the NIH (P50HD103555); BCM start-up funds; Albert and Margaret Alkek Foundation; McNair Medical Institute; Robert and Janice McNair Foundation; BCM Seed Funding (1P20CA221731-01A1); National Institute of General Medical Sciences (R01 GM120033); Cynthia and Antony Petrello Endowment; Mark A. Wallace Endowment; McKnight Foundation; Dana Foundation; BCM Computational and Integrative Biomedical Research Center seed grant.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	TLX ; NR2E1 ; Fatty acids ; Neural stem/progenitor cells ; Neurogenesis
Publicat a:	Proceedings of the National Academy of Sciences of the United States of America, Vol. 119 Núm. 13 (March 2022) , p. e2023784119, ISSN 1091-6490

DOI: 10.1073/pnas.2023784119
PMID: 35333654

11 p, 2.5 MB

El registre apareix a les col·leccions:
Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut de Recerca Sant Pau
Articles > Articles de recerca
Articles > Articles publicats