Biology:N2a cell

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N2a cells (also known as Neuro2a cells) are a fast-growing mouse neuroblastoma cell line.[1]

Differentiation properties

Originating from a mouse, the N2a cell line has a neuronal and amoeboid stem cell morphology, allowing it to differentiate in response to environmental factors. The differentiated cells have many properties of neurons, including neurofilaments. The differentiation of N2a cells is caused by activation of the mitogen-activated protein kinase/extracellular-signal regulated kinase (MAPK/ERK) and the phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling pathways.[1] The cells, due to passaging since initial collection, can exhibit responses to toxins that differ from those of neuronal cells in a live organism.[2] Synthesizing large amounts of microtubules, N2a cells are susceptible to viruses (such as herpes simplex and poliovirus) that can alter cell morphology and physiology.

Factors that Affect Differentiation of N2a Cells

Promoting Factors

  • Emodin causes N2a differentiation and growth through activation of the PI3K/Akt pathway. It does so by activating Akt while inactivating glycogen synthase kinase-3β (GSK-3β), an inhibitor of the Akt pathway. Emodin specifically causes phosphorylation of cAMP-responsive element binding protein (CREB), an important molecule in the differentiation of neurons.[3]
  • β-Hydroxy-β-methylbutyrate (HMB) causes N2a growth through activation and phosphorylation of the PI3K/Akt and MAPK/ERK signaling pathways. HMB causes activation of mTOR, which is regulated by the Atk pathway, and expression of glucose transporters in N2a cells, leading to differentiation. It also increases the activity of MEF2, mainly MEF2C, in N2a cells.[1]
  • α-lipoic acid (LA) mainly causes N2a differentiation through phosphorylation of the ERK pathway and the Akt pathway. Inhibition of only the ERK pathway will prevent LA-induced differentiation from occurring, while inhibition of the Akt pathway will not prevent LA-induced differentiation. LA causes differentiation through the production of reactive oxygen species which activate the ERK pathway.[4]

Inhibitory Factors

  • High density lipoproteins (HDL) inhibit differentiation of N2a cells that are differentiated through serum-withdrawal differentiation. HDL does so through inhibiting the function of epidermal growth factor receptor (EGFR) by preventing EGFR phosphorylation. This prevents EGFR from causing activation of the Akt and ERK pathways.[5]
  • Avermectin (AVM) derivatives abamectin (ABM) and doramectin (DOM) inhibit N2a differentiation by suppressing P-glycoprotein (P-gp) in N2a cells, a major contributor to N2a cell differentiation.[6]

Research applications

N2a cells are able to rapidly, reliably, and easily differentiate,[7] making them effective for use in research applications relating to neurons and neuronal disorders. Serum withdrawal is a common method of inducing differentiation of N2a cells, involving removal of the serum that the cells are grown in to activate the signaling pathways governing differentiation.[5] N2a cells have been used to study neurite outgrowth,[1] neurotoxicity,[2] Alzheimer's disease,[8] asymmetric division of mammalian cell lines,[9] adenoviral transduction, and the diagnosing of rabies. One specific research applications is the differentiation of N2a cells into dopamine neurons for potential use in treating Parkinson's Disease.

References

  1. ↑ 1.0 1.1 1.2 1.3 Salto, Rafael; Vílchez, Jose D.; Girón, María D.; Cabrera, Elena; Campos, Nefertiti; Manzano, Manuel; Rueda, Ricardo; López-Pedrosa, Jose M. (2015-08-12). "β-Hydroxy-β-Methylbutyrate (HMB) Promotes Neurite Outgrowth in Neuro2a Cells" (in en). PLOS ONE 10 (8): e0135614. doi:10.1371/journal.pone.0135614. ISSN 1932-6203. PMID 26267903. 
  2. ↑ 2.0 2.1 "On the use of neuro-2a neuroblastoma cells versus intact neurons in primary culture for neurotoxicity studies". Critical Reviews in Neurobiology 17 (1): 27–50. 2005. doi:10.1615/critrevneurobiol.v17.i1.20. PMID 16307526. 
  3. ↑ Park, Shin-Ji; Jin, Mei Ling; An, Hyun-Kyu; Kim, Kyoung-Sook; Ko, Min Jung; Kim, Cheol Min; Choi, Young Whan; Lee, Young-Choon (2015-02-19). "Emodin induces neurite outgrowth through PI3K/Akt/GSK-3β-mediated signaling pathways in Neuro2a cells" (in en). Neuroscience Letters 588: 101–107. doi:10.1016/j.neulet.2015.01.001. ISSN 0304-3940. https://www.sciencedirect.com/science/article/pii/S0304394015000063. 
  4. ↑ Wang, Xiaohui; Wang, Zhuyao; Yao, Yuzhen; Li, Jingjin; Zhang, Xiaojin; Li, Chuanfu; Cheng, Yunlin; Ding, Guoxian et al. (2011-05-01). "Essential role of ERK activation in neurite outgrowth induced by α-lipoic acid" (in en). Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. Including the Special Section: 11th European Symposium on Calcium 1813 (5): 827–838. doi:10.1016/j.bbamcr.2011.01.027. ISSN 0167-4889. https://www.sciencedirect.com/science/article/pii/S0167488911000358. 
  5. ↑ 5.0 5.1 Evangelopoulos, Maria Elephteria; Weis, Joachim; Krüttgen, Alex (2005-05-05). "Signalling pathways leading to neuroblastoma differentiation after serum withdrawal: HDL blocks neuroblastoma differentiation by inhibition of EGFR" (in en). Oncogene 24 (20): 3309–3318. doi:10.1038/sj.onc.1208494. ISSN 1476-5594. https://www.nature.com/articles/1208494. 
  6. ↑ Sun, Ying-Jian; Long, Ding-Xin; Li, Wei; Hou, Wei-Yuan; Wu, Yi-Jun; Shen, Jian-Zhong (2010-02-01). "Effects of avermectins on neurite outgrowth in differentiating mouse neuroblastoma N2a cells" (in en). Toxicology Letters 192 (2): 206–211. doi:10.1016/j.toxlet.2009.10.021. ISSN 0378-4274. https://www.sciencedirect.com/science/article/pii/S0378427409014763. 
  7. ↑ Tremblay, Roger G.; Sikorska, Marianna; Sandhu, Jagdeep K.; Lanthier, Patricia; Ribecco-Lutkiewicz, Maria; Bani-Yaghoub, Mahmud (2010-01-30). "Differentiation of mouse Neuro 2A cells into dopamine neurons" (in en). Journal of Neuroscience Methods 186 (1): 60–67. doi:10.1016/j.jneumeth.2009.11.004. ISSN 0165-0270. https://www.sciencedirect.com/science/article/pii/S0165027009006025. 
  8. ↑ Provost P (2010). "Interpretation and applicability of microRNA data to the context of Alzheimer's and age-related diseases". Aging 2 (3): 166–169. doi:10.18632/aging.100131. PMID 20375468. PMC 871245. https://www.aging-us.com/article/100131/text. 
  9. ↑ "Dynamic JUNQ inclusion bodies are asymmetrically inherited in mammalian cell lines through the asymmetric partitioning of vimentin". Proceedings of the National Academy of Sciences of the United States of America 111 (22): 8049–54. 2014. doi:10.1073/pnas.1324035111. PMID 24843142. Bibcode: 2014PNAS..111.8049O. 

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