Fat Mass and Obesity-associated (FTO) Protein Regulates Adult Neurogenesis

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2017 Apr 12

PMID 28398475

Citations 166

Authors

Liping Li

Liqun Zang

Feiran Zhang

Junchen Chen

Hui Shen

Liqi Shu

Feng Liang

Chunyue Feng

Deng Chen

Huikang Tao

Tianlei Xu

Ziyi Li

Yunhee Kang

Hao Wu

Lichun Tang

Pumin Zhang

Peng Jin

Qiang Shu

Xuekun Li

Affiliations

Soon will be listed here.

Abstract

Fat mass and obesity-associated gene (FTO) is a member of the Fe (II)- and oxoglutarate-dependent AlkB dioxygenase family and is linked to both obesity and intellectual disability. The role of FTO in neurodevelopment and neurogenesis, however, remains largely unknown. Here we show that FTO is expressed in adult neural stem cells and neurons and displays dynamic expression during postnatal neurodevelopment. The loss of FTO leads to decreased brain size and body weight. We find that FTO deficiency could reduce the proliferation and neuronal differentiation of adult neural stem cells in vivo, which leads to impaired learning and memory. Given the role of FTO as a demethylase of N6-methyladenosine (m6A), we went on to perform genome-wide m6A profiling and observed dynamic m6A modification during postnatal neurodevelopment. The loss of FTO led to the altered expression of several key components of the brain derived neurotrophic factor pathway that were marked by m6A. These results together suggest FTO plays important roles in neurogenesis, as well as in learning and memory.

Citing Articles

Neural stem cell heterogeneity in adult hippocampus.

Liang Z, Jin N, Guo W Cell Regen. 2025; 14(1):6.

PMID: 40053275 PMC: 11889326. DOI: 10.1186/s13619-025-00222-4.

FTO inhibition mitigates high-fat diet-induced metabolic disturbances and cognitive decline in SAMP8 mice.

Irisarri A, Corral A, Perez-Salvador N, Bellver-Sanchis A, Ribalta-Vilella M, Bentanachs R Mol Med. 2025; 31(1):73.

PMID: 39984825 PMC: 11843768. DOI: 10.1186/s10020-025-01126-4.

Mettl3-mA-NPY axis governing neuron-microglia interaction regulates sleep amount of mice.

Sun Q, Zhu J, Zhao X, Huang X, Qu W, Tang X Cell Discov. 2025; 11(1):10.

PMID: 39905012 PMC: 11794856. DOI: 10.1038/s41421-024-00756-y.

Novel role of FTO in regulation of gut-brain communication via -produced hydrogen sulfide under arsenic exposure.

Chen R, Chai X, Zhang Y, Zhou T, Xia Y, Jiang X Gut Microbes. 2025; 17(1):2438471.

PMID: 39852343 PMC: 11776478. DOI: 10.1080/19490976.2024.2438471.

Overexpression of FTO alleviates traumatic brain injury induced posttraumatic epilepsy by upregulating NR4A2 expression via m6A demethylation.

Xiao M, Wang X, Xiao E, Ming Q Funct Integr Genomics. 2025; 25(1):17.

PMID: 39825968 DOI: 10.1007/s10142-024-01522-9.

References

Nainar S, Marshall P, Tyler C, Spitale R, Bredy T . Evolving insights into RNA modifications and their functional diversity in the brain. Nat Neurosci. 2016; 19(10):1292-8. PMC: 5068363. DOI: 10.1038/nn.4378. View

Meyer K, Jaffrey S . The dynamic epitranscriptome: N6-methyladenosine and gene expression control. Nat Rev Mol Cell Biol. 2014; 15(5):313-26. PMC: 4393108. DOI: 10.1038/nrm3785. View

Huang D, Sherman B, Lempicki R . Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4(1):44-57. DOI: 10.1038/nprot.2008.211. View

Hess M, Hess S, Meyer K, Verhagen L, Koch L, Bronneke H . The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry. Nat Neurosci. 2013; 16(8):1042-8. DOI: 10.1038/nn.3449. View

Niu Y, Zhao X, Wu Y, Li M, Wang X, Yang Y . N6-methyl-adenosine (m6A) in RNA: an old modification with a novel epigenetic function. Genomics Proteomics Bioinformatics. 2013; 11(1):8-17. PMC: 4357660. DOI: 10.1016/j.gpb.2012.12.002. View

Avgustinova A, Benitah S . Epigenetic control of adult stem cell function. Nat Rev Mol Cell Biol. 2016; 17(10):643-58. DOI: 10.1038/nrm.2016.76. View

Kuipers S, Trentani A, Tiron A, Mao X, Kuhl D, Bramham C . BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis. Sci Rep. 2016; 6:21222. PMC: 4758047. DOI: 10.1038/srep21222. View

Gao Y, Su J, Guo W, Polich E, Magyar D, Xing Y . Inhibition of miR-15a Promotes BDNF Expression and Rescues Dendritic Maturation Deficits in MeCP2-Deficient Neurons. Stem Cells. 2015; 33(5):1618-29. PMC: 4409556. DOI: 10.1002/stem.1950. View

Li X, Jin P . Roles of small regulatory RNAs in determining neuronal identity. Nat Rev Neurosci. 2010; 11(5):329-38. DOI: 10.1038/nrn2739. View

10.

Haussmann I, Bodi Z, Sanchez-Moran E, Mongan N, Archer N, Fray R . mA potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature. 2016; 540(7632):301-304. DOI: 10.1038/nature20577. View

11.

Zimmermann T, Remmers F, Lutz B, Leschik J . ESC-Derived BDNF-Overexpressing Neural Progenitors Differentially Promote Recovery in Huntington's Disease Models by Enhanced Striatal Differentiation. Stem Cell Reports. 2016; 7(4):693-706. PMC: 5063570. DOI: 10.1016/j.stemcr.2016.08.018. View

12.

Deng W, Aimone J, Gage F . New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?. Nat Rev Neurosci. 2010; 11(5):339-50. PMC: 2886712. DOI: 10.1038/nrn2822. View

13.

Carroll S, Narayan P, ROTTMAN F . N6-methyladenosine residues in an intron-specific region of prolactin pre-mRNA. Mol Cell Biol. 1990; 10(9):4456-65. PMC: 361031. DOI: 10.1128/mcb.10.9.4456-4465.1990. View

14.

Meng J, Cui X, Rao M, Chen Y, Huang Y . Exome-based analysis for RNA epigenome sequencing data. Bioinformatics. 2013; 29(12):1565-7. PMC: 3673212. DOI: 10.1093/bioinformatics/btt171. View

15.

Trapnell C, Hendrickson D, Sauvageau M, Goff L, Rinn J, Pachter L . Differential analysis of gene regulation at transcript resolution with RNA-seq. Nat Biotechnol. 2012; 31(1):46-53. PMC: 3869392. DOI: 10.1038/nbt.2450. View

16.

Geula S, Moshitch-Moshkovitz S, Dominissini D, AlFatah Mansour A, Kol N, Salmon-Divon M . Stem cells. m6A mRNA methylation facilitates resolution of naïve pluripotency toward differentiation. Science. 2015; 347(6225):1002-6. DOI: 10.1126/science.1261417. View

17.

Boschen K, McKeown S, Roth T, Klintsova A . Impact of exercise and a complex environment on hippocampal dendritic morphology, Bdnf gene expression, and DNA methylation in male rat pups neonatally exposed to alcohol. Dev Neurobiol. 2016; 77(6):708-725. PMC: 5997455. DOI: 10.1002/dneu.22448. View

18.

Dominissini D, Moshitch-Moshkovitz S, Salmon-Divon M, Amariglio N, Rechavi G . Transcriptome-wide mapping of N(6)-methyladenosine by m(6)A-seq based on immunocapturing and massively parallel sequencing. Nat Protoc. 2013; 8(1):176-89. DOI: 10.1038/nprot.2012.148. View

19.

Fu Y, Dominissini D, Rechavi G, He C . Gene expression regulation mediated through reversible m⁶A RNA methylation. Nat Rev Genet. 2014; 15(5):293-306. DOI: 10.1038/nrg3724. View

20.

Yue Y, Liu J, He C . RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015; 29(13):1343-55. PMC: 4511210. DOI: 10.1101/gad.262766.115. View