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. 2012 Dec 7;28(6):669–679. doi: 10.1007/s12264-012-1288-5

Bcl-2 enhances the formation of newborn striatal long-projection neurons in adult rat brain after a transient ischemic stroke

Jian-Jun Guo 1,2, Fang Liu 1,2, Xiao Sun 1,2, Jun-Jie Huang 1,2, Ming Xu 1,2, Feng-Yan Sun 1,2,✉
PMCID: PMC5561824  PMID: 23225311

Abstract

Objective

It has been reported that B-cell lymphoma 2 (Bcl-2) enhances neurogenesis as well as supporting axonal growth after injury. In the present study, we investigated whether Bcl-2 overexpression plays a role in the formation of newborn striatonigral projection neurons in the adult rat brain after transient middle cerebral artery occlusion (MCAO).

Methods

We infused human Bcl-2-expressing plasmid (pBcl-2) into the lateral ventricle immediately after 30 min of MCAO, injected 5′-bromodeoxyuridine (BrdU) intraperitoneally to label proliferative cells, and microinjected fluorogold (FG) into the substantia nigra at 11 weeks of reperfusion followed by multiple immunostaining of striatonigral projection neurons at 12 weeks.

Results

We found that pBcl-2 treatment significantly increased the number of newborn neurons (BrdU+-NeuN+) in the striatum ipsilateral to the MCAO. We further detected newborn striatonigral projection neurons (BrdU+-FG+-NeuN+) in the ipsilateral striatum at 12 weeks. More interestingly, the number of newborn striatonigral projection neurons (BrdU+-FG+) was significantly increased by pBcl-2 treatment compared to that by pEGFP, a control plasmid.

Conclusion

Taken together, we found that Bcl-2 overexpression in the brain enhanced the generation of newborn striatonigral projection neurons. This provides a potential strategy for promoting the reestablishment of neural networks and brain repair after ischemic injury.

Keywords: cerebral ischemia, Bcl-2, striatonigral projection neuron, neurogenesis, brain repair

References

  • [1].Abrous D.N., Koehl M., Le Moal M. Adult neurogenesis: from precursors to network and physiology. Physiol Rev. 2005;85:523–569. doi: 10.1152/physrev.00055.2003. [DOI] [PubMed] [Google Scholar]
  • [2].Taupin P., Gage F.H. Adult neurogenesis and neural stem cells of the central nervous system in mammals. J Neurosci Res. 2002;69:745–749. doi: 10.1002/jnr.10378. [DOI] [PubMed] [Google Scholar]
  • [3].Ma D.K., Bonaguidi M.A., Ming G.L., Song H. Adult neural stem cells in the mammalian central nervous system. Cell Res. 2009;19:672–682. doi: 10.1038/cr.2009.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [4].Jin K., Sun Y., Xie L., Peel A., Mao X.O., Batteur S., et al. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Mol Cell Neurosci. 2003;24:171–189. doi: 10.1016/S1044-7431(03)00159-3. [DOI] [PubMed] [Google Scholar]
  • [5].Arvidsson A., Collin T., Kirik D., Kokaia Z., Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–970. doi: 10.1038/nm747. [DOI] [PubMed] [Google Scholar]
  • [6].Hou S.W., Wang Y.Q., Xu M., Shen D.H., Wang J.J., Huang F., et al. Functional integration of newly generated neurons into striatum after cerebral ischemia in the adult rat brain. Stroke. 2008;39:2837–2844. doi: 10.1161/STROKEAHA.107.510982. [DOI] [PubMed] [Google Scholar]
  • [7].Lindvall O., Kokaia Z. Stem cells in human neurodegenerative disorders—time for clinical translation? J Clin Invest. 2010;120:29–40. doi: 10.1172/JCI40543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [8].Sun X., Zhang Q.W., Xu M., Guo J.J., Shen S.W., Wang Y.Q., et al. New striatal neurons form projections to substantia nigra in adult rat brain after stroke. Neurobiol Dis. 2012;45:601–609. doi: 10.1016/j.nbd.2011.09.018. [DOI] [PubMed] [Google Scholar]
  • [9].Zhang R., Xue Y.Y., Lu S.D., Wang Y., Zhang L.M., Huang Y.L., et al. Bcl-2 enhances neurogenesis and inhibits apoptosis of newborn neurons in adult rat brain following a transient middle cerebral artery occlusion. Neurobiol Dis. 2006;24:345–356. doi: 10.1016/j.nbd.2006.07.012. [DOI] [PubMed] [Google Scholar]
  • [10].Jin K., Zhu Y., Sun Y., Mao X.O., Xie L., Greenberg D.A. Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc Natl Acad Sci U S A. 2002;99:11946–11950. doi: 10.1073/pnas.182296499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [11].Wang Y.Q., Guo X., Qiu M.H., Feng X.Y., Sun F.Y. VEGF overexpression enhances striatal neurogenesis in brain of adult rat after a transient middle cerebral artery occlusion. J Neurosci Res. 2007;85:73–82. doi: 10.1002/jnr.21091. [DOI] [PubMed] [Google Scholar]
  • [12].Wang Y.Q., Cui H.R., Yang S.Z., Sun H.P., Qiu M.H., Feng X.Y., et al. VEGF enhance cortical newborn neurons and their neurite development in adult rat brain after cerebral ischemia. Neurochem Int. 2009;55:629–636. doi: 10.1016/j.neuint.2009.06.007. [DOI] [PubMed] [Google Scholar]
  • [13].Yoshikawa G., Momiyama T., Oya S., Takai K., Tanaka J., Higashiyama S., et al. Induction of striatal neurogenesis and generation of regionspecific functional mature neurons after ischemia by growth factors. Laboratory investigation. J Neurosurg. 2010;113:835–850. doi: 10.3171/2010.2.JNS09989. [DOI] [PubMed] [Google Scholar]
  • [14].Tagami S., Eguchi Y., Kinoshita M., Takeda M., Tsujimoto Y. A novel protein, RTN-XS, interacts with both Bcl-XL and Bcl-2 on endoplasmic reticulum and reduces their anti-apoptotic activity. Oncogene. 2000;19:5736–5746. doi: 10.1038/sj.onc.1203948. [DOI] [PubMed] [Google Scholar]
  • [15].Tsujimoto Y., Finger L.R., Yunis J., Nowell P.C., Croce C.M. Cloning of the chromosome breakpoint of neoplastic B cells with the t(14;18) chromosome translocation. Science. 1984;226:1097–1099. doi: 10.1126/science.6093263. [DOI] [PubMed] [Google Scholar]
  • [16].Cleary M.L., Smith S.D., Sklar J. Cloning and structural analysis of cDNAs for bcl-2 and a hybrid bcl-2/immunoglobulin transcript resulting from the t(14;18) translocation. Cell. 1986;47:19–28. doi: 10.1016/0092-8674(86)90362-4. [DOI] [PubMed] [Google Scholar]
  • [17].Abe-Dohmae S., Harada N., Yamada K., Tanaka R. Bcl-2 gene is highly expressed during neurogenesis in the central nervous system. Biochem Biophys Res Commun. 1993;191:915–921. doi: 10.1006/bbrc.1993.1304. [DOI] [PubMed] [Google Scholar]
  • [18].Ferrer I., Tortosa A., Condom E., Blanco R., Macaya A., Planas A. Increased expression of bcl-2 immunoreactivity in the developing cerebral cortex of the rat. Neurosci Lett. 1994;179:13–16. doi: 10.1016/0304-3940(94)90923-7. [DOI] [PubMed] [Google Scholar]
  • [19].Bernier P.J., Vinet J., Cossette M., Parent A. Characterization of the subventricular zone of the adult human brain: evidence for the involvement of Bcl-2. Neurosci Res. 2000;37:67–78. doi: 10.1016/S0168-0102(00)00102-4. [DOI] [PubMed] [Google Scholar]
  • [20].Lei Z.N., Liu F., Zhang L.M., Huang Y.L., Sun F.Y. Bcl-2 increases stroke-induced striatal neurogenesis in adult brains by inhibiting BMP-4 function via activation of β-catenin signaling. Neurochem Int. 2012;61:34–42. doi: 10.1016/j.neuint.2012.04.004. [DOI] [PubMed] [Google Scholar]
  • [21].Chen D.F., Schneider G.E., Martinou J.C., Tonegawa S. Bcl-2 promotes regeneration of severed axons in mammalian CNS. Nature. 1997;385:434–439. doi: 10.1038/385434a0. [DOI] [PubMed] [Google Scholar]
  • [22].Holm K.H., Cicchetti F., Bjorklund L., Boonman Z., Tandon P., Costantini L.C., et al. Enhanced axonal growth from fetal human bcl-2 transgenic mouse dopamine neurons transplanted to the adult rat striatum. Neuroscience. 2001;104:397–405. doi: 10.1016/S0306-4522(01)00098-7. [DOI] [PubMed] [Google Scholar]
  • [23].Hilton M., Middleton G., Davies A.M. Bcl-2 influences axonal growth rate in embryonic sensory neurons. Curr Biol. 1997;7:798–800. doi: 10.1016/S0960-9822(06)00339-3. [DOI] [PubMed] [Google Scholar]
  • [24].Cao Y.J., Shibata T., Rainov N.G. Liposome-mediated transfer of the bcl-2 gene results in neuroprotection after in vivo transient focal cerebral ischemia in an animal model. Gene Ther. 2002;9:415–419. doi: 10.1038/sj.gt.3301676. [DOI] [PubMed] [Google Scholar]
  • [25].Sugiura S., Kitagawa K., Tanaka S., Todo K., Omura-Matsuoka E., Sasaki T., et al. Adenovirus-mediated gene transfer of heparin-bind ing epidermal growth factor-like growth factor enhances neurogenesis and angiogenesis after focal cerebral ischemia in rats. Stroke. 2005;36:859–864. doi: 10.1161/01.STR.0000158905.22871.95. [DOI] [PubMed] [Google Scholar]
  • [26].Paxinos G., Watson C. The Rat Brain in Stereotaxic Coordinates. Sydney: Academic Press; 2006. [Google Scholar]
  • [27].Liu J., Solway K., Messing R.O., Sharp F.R. Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J Neurosci. 1998;18:7768–7778. doi: 10.1523/JNEUROSCI.18-19-07768.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Liu P.C., Lu S.D., Huang Y.L., Sun F.Y. The expression of nestin in ischemia-injured brain of adult rat. Acta Physiol Sin. 2002;54:294–299. [PubMed] [Google Scholar]
  • [29].Yang SZ, Li KY, Wang YQ, Shen DH, Sun FY. Functional contribution of neurogenesis in normal and stroke brain. Adult Neurogenesis Cent Nerv Syst Dis 2010:91–125.
  • [30].Jiao J., Huang X., Feit-Leithman R.A., Neve R.L., Snider W., Dartt D.A., et al. Bcl-2 enhances Ca(2+) signaling to support the intrinsic regenerative capacity of CNS axons. EMBO J. 2005;24:1068–1078. doi: 10.1038/sj.emboj.7600589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Suzuki A., Tsutomi Y. Bcl-2 accelerates the neuronal differentiation: new evidence approaching to the biofunction of bcl-2 in the neuronal system. Brain Res. 1998;801:59–66. doi: 10.1016/S0006-8993(98)00523-X. [DOI] [PubMed] [Google Scholar]

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