Lethal Phenotype-Based Database Screening Identifies Ceramide As a Negative Regulator of Primitive Streak Formation

Overview

Journal Stem Cells

Publisher Oxford University Press

Specialties Cell Biology
Reproductive Medicine

Date 2023 Oct 11

PMID 37819786

Authors

Jing Pu

Satoshi Kofuji

Yoshimi Okamoto-Uchida

Keiko Danzaki

Ruoxing Yu

Akira Suzuki

Satoshi Kitajima

Hiroshi Nishina

Affiliations

Soon will be listed here.

Abstract

In early embryogenesis, the primitive streak (PrS) generates the mesendoderm and is essential for organogenesis. However, because the PrS is a minute and transient tissue, elucidating the mechanism of its formation has been challenging. We performed comprehensive screening of 2 knockout mouse databases based on the fact that failure of PrS formation is lethal. We identified 812 genes involved in various cellular functions and responses that might be linked to PrS formation, with the category of greatest abundance being "Metabolism." In this study, we focused on genes of sphingolipid metabolism and investigated their roles in PrS formation using an in vitro mouse ES cell differentiation system. We show here that elevated intracellular ceramide negatively regulates gene expression essential for PrS formation and instead induces neurogenesis. In addition, sphingosine-1-phosphate (a ceramide derivative) positively regulates neural maturation. Our results indicate that ceramide regulates both PrS formation and the induction of neural differentiation.

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References

Wu J, Kubota J, Hirayama J, Nagai Y, Nishina S, Yokoi T . p38 Mitogen-activated protein kinase controls a switch between cardiomyocyte and neuronal commitment of murine embryonic stem cells by activating myocyte enhancer factor 2C-dependent bone morphogenetic protein 2 transcription. Stem Cells Dev. 2010; 19(11):1723-34. DOI: 10.1089/scd.2010.0066. View

Desbaillets I, Ziegler U, Groscurth P, Gassmann M . Embryoid bodies: an in vitro model of mouse embryogenesis. Exp Physiol. 2001; 85(6):645-51. View

Zhu G, Ying Y, Ji K, Duan X, Mai T, Kim J . p53 coordinates glucose and choline metabolism during the mesendoderm differentiation of human embryonic stem cells. Stem Cell Res. 2020; 49:102067. DOI: 10.1016/j.scr.2020.102067. View

Shimizu N, Watanabe H, Kubota J, Wu J, Saito R, Yokoi T . Pax6-5a promotes neuronal differentiation of murine embryonic stem cells. Biol Pharm Bull. 2009; 32(6):999-1003. DOI: 10.1248/bpb.32.999. View

Wang G, Krishnamurthy K, Chiang Y, Dasgupta S, Bieberich E . Regulation of neural progenitor cell motility by ceramide and potential implications for mouse brain development. J Neurochem. 2008; 106(2):718-33. PMC: 3812674. DOI: 10.1111/j.1471-4159.2008.05451.x. View

Wadsworth J, Clarke D, McMahon S, Lowther J, Beattie A, Langridge-Smith P . The chemical basis of serine palmitoyltransferase inhibition by myriocin. J Am Chem Soc. 2013; 135(38):14276-85. DOI: 10.1021/ja4059876. View

Gonzalez J, Morgani S, Bone R, Bonderup K, Abelchian S, Brakebusch C . Embryonic Stem Cell Culture Conditions Support Distinct States Associated with Different Developmental Stages and Potency. Stem Cell Reports. 2016; 7(2):177-91. PMC: 4983099. DOI: 10.1016/j.stemcr.2016.07.009. View

Bain G, Kitchens D, Yao M, Huettner J, Gottlieb D . Embryonic stem cells express neuronal properties in vitro. Dev Biol. 1995; 168(2):342-57. DOI: 10.1006/dbio.1995.1085. View

Ramkumar N, Anderson K . SnapShot: mouse primitive streak. Cell. 2011; 146(3):488-488.e2. DOI: 10.1016/j.cell.2011.07.028. View

10.

Boheler K, Czyz J, Tweedie D, Yang H, Anisimov S, Wobus A . Differentiation of pluripotent embryonic stem cells into cardiomyocytes. Circ Res. 2002; 91(3):189-201. DOI: 10.1161/01.res.0000027865.61704.32. View

11.

Bieberich E . Ceramide signaling in cancer and stem cells. Future Lipidol. 2008; 3(3):273-300. PMC: 2493052. DOI: 10.2217/17460875.3.3.273. View

12.

Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H . Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002; 3(6):889-901. DOI: 10.1016/s1534-5807(02)00369-6. View

13.

Li C, Park J, Simonaro C, He X, Gordon R, Ehleiter D . Insertional mutagenesis of the mouse acid ceramidase gene leads to early embryonic lethality in homozygotes and progressive lipid storage disease in heterozygotes. Genomics. 2002; 79(2):218-24. DOI: 10.1006/geno.2002.6686. View

14.

Yamasaki T, Kawasaki H, Arakawa S, Shimizu K, Shimizu S, Reiner O . Stress-activated protein kinase MKK7 regulates axon elongation in the developing cerebral cortex. J Neurosci. 2011; 31(46):16872-83. PMC: 6633308. DOI: 10.1523/JNEUROSCI.1111-11.2011. View

15.

Itskovitz-Eldor J, Schuldiner M, Karsenti D, Eden A, Yanuka O, Amit M . Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med. 2000; 6(2):88-95. PMC: 1949933. View

16.

Cliff T, Wu T, Boward B, Yin A, Yin H, Glushka J . MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux. Cell Stem Cell. 2017; 21(4):502-516.e9. PMC: 5644510. DOI: 10.1016/j.stem.2017.08.018. View

17.

Ohashi K, Osuga J, Tozawa R, Kitamine T, Yagyu H, Sekiya M . Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. J Biol Chem. 2003; 278(44):42936-41. DOI: 10.1074/jbc.M307228200. View

18.

Arima N, Uchida Y, Yu R, Nakayama K, Nishina H . Acetylcholine receptors regulate gene expression that is essential for primitive streak formation in murine embryoid bodies. Biochem Biophys Res Commun. 2013; 435(3):447-53. DOI: 10.1016/j.bbrc.2013.05.006. View

19.

Platt F, Neises G, Dwek R, Butters T . N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J Biol Chem. 1994; 269(11):8362-5. View

20.

Mijimolle N, Velasco J, Dubus P, Guerra C, Weinbaum C, Casey P . Protein farnesyltransferase in embryogenesis, adult homeostasis, and tumor development. Cancer Cell. 2005; 7(4):313-24. DOI: 10.1016/j.ccr.2005.03.004. View