Transcriptional Responses of Different Brain Cell Types to Oxygen Decline

Overview

Journal Brain Sci

Publisher MDPI

Date 2024 Apr 27

PMID 38671993

Authors

Camille Ravel-Godreuil

Ethan R Roy

Srinivas N Puttapaka

Sanming Li

Yanyu Wang

Xiaoyi Yuan

Holger K Eltzschig

Wei Cao

Affiliations

Soon will be listed here.

Abstract

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells. Analysis of differentially expressed genes under conditions of reduced oxygen revealed a canonical hypoxic response shared among different brain cell types. In addition, we observed a higher sensitivity of neurons to oxygen decline, and dissected cell type-specific biological processes affected by hypoxia. Importantly, this study establishes novel gene modules associated with brain cells responding to oxygen deprivation and reveals a state of profound stress incurred by hypoxia.

References

Hubbi M, Semenza G . Regulation of cell proliferation by hypoxia-inducible factors. Am J Physiol Cell Physiol. 2015; 309(12):C775-82. PMC: 4683214. DOI: 10.1152/ajpcell.00279.2015. View

Manella G, Aviram R, Bolshette N, Muvkadi S, Golik M, Smith D . Hypoxia induces a time- and tissue-specific response that elicits intertissue circadian clock misalignment. Proc Natl Acad Sci U S A. 2019; 117(1):779-786. PMC: 6955294. DOI: 10.1073/pnas.1914112117. View

Druker J, Wilson J, Child F, Shakir D, Fasanya T, Rocha S . Role of Hypoxia in the Control of the Cell Cycle. Int J Mol Sci. 2021; 22(9). PMC: 8124716. DOI: 10.3390/ijms22094874. View

Li F, Qiao Z, Duan Q, Nevo E . Adaptation of mammals to hypoxia. Animal Model Exp Med. 2022; 4(4):311-318. PMC: 8690989. DOI: 10.1002/ame2.12189. View

Semenza G . Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012; 33(4):207-14. PMC: 3437546. DOI: 10.1016/j.tips.2012.01.005. View

Pan C, Garriga G . Fresh air is good for nerves: hypoxia disturbs axon guidance. Nat Neurosci. 2008; 11(8):859-61. DOI: 10.1038/nn0808-859. View

Vasile F, Dossi E, Rouach N . Human astrocytes: structure and functions in the healthy brain. Brain Struct Funct. 2017; 222(5):2017-2029. PMC: 5504258. DOI: 10.1007/s00429-017-1383-5. View

Palazon A, Goldrath A, Nizet V, Johnson R . HIF transcription factors, inflammation, and immunity. Immunity. 2014; 41(4):518-28. PMC: 4346319. DOI: 10.1016/j.immuni.2014.09.008. View

Copple B, Bai S, Burgoon L, Moon J . Hypoxia-inducible factor-1α regulates the expression of genes in hypoxic hepatic stellate cells important for collagen deposition and angiogenesis. Liver Int. 2010; 31(2):230-44. PMC: 3099214. DOI: 10.1111/j.1478-3231.2010.02347.x. View

10.

Baek G, Tse Y, Hu Z, Cox D, Buboltz N, McCue P . MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies. Cell Rep. 2014; 9(6):2233-49. DOI: 10.1016/j.celrep.2014.11.025. View

11.

Mukamel E, Ngai J . Perspectives on defining cell types in the brain. Curr Opin Neurobiol. 2018; 56:61-68. PMC: 6551297. DOI: 10.1016/j.conb.2018.11.007. View

12.

Kaelin Jr W . Von Hippel-Lindau disease: insights into oxygen sensing, protein degradation, and cancer. J Clin Invest. 2022; 132(18). PMC: 9479583. DOI: 10.1172/JCI162480. View

13.

Jia L, Liang T, Yu X, Ma C, Zhang S . MGARP regulates mouse neocortical development via mitochondrial positioning. Mol Neurobiol. 2013; 49(3):1293-308. DOI: 10.1007/s12035-013-8602-8. View

14.

Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouyssegur J . Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009; 29(10):2570-81. PMC: 2682037. DOI: 10.1128/MCB.00166-09. View

15.

Sher P . Chronic hypoxia in neuronal cell culture: metabolic consequences. Brain Dev. 1990; 12(3):293-300. DOI: 10.1016/s0387-7604(12)80309-3. View

16.

Wang G, Semenza G . General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proc Natl Acad Sci U S A. 1993; 90(9):4304-8. PMC: 46495. DOI: 10.1073/pnas.90.9.4304. View

17.

Ail D, Samardzija M, Chang A, Keck J, Reddel R, Grimm C . , but Not , Responds to Hypoxia in a HIF1-Dependent Manner in the Retina. Front Neurosci. 2022; 16:882559. PMC: 9259883. DOI: 10.3389/fnins.2022.882559. View

18.

Leppa S, Bohmann D . Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene. 1999; 18(45):6158-62. DOI: 10.1038/sj.onc.1203173. View

19.

Halterman M, Gill M, DeJesus C, Ogihara M, Schor N, Federoff H . The endoplasmic reticulum stress response factor CHOP-10 protects against hypoxia-induced neuronal death. J Biol Chem. 2010; 285(28):21329-40. PMC: 2898390. DOI: 10.1074/jbc.M109.095299. View

20.

Wang G, Jiang B, Rue E, Semenza G . Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995; 92(12):5510-4. PMC: 41725. DOI: 10.1073/pnas.92.12.5510. View