Skip to main content

Advertisement

SpringerLink
Log in

Increased Cell Proliferations and Neurogenesis in the Hippocampal Dentate Gyrus of Ahnak Deficient Mice

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Expression of the giant protein Ahnak has been reported in endothelial cells of the blood brain barrier and in non-neuronal cells including myelinating Schwann cells. However, the function of Ahnak in neurogenesis has not been determined. In the present study, we report for the first time the effects of Ahnak on adult hippocampal neurogenesis using Ahnak−/− mice. Proliferating cells were labeled with BrdU for a 30-day period before sacrifice. In Ahnak−/− mice, the incorporation of BrdU with NeuN (Neuronal Nuclei) increased significantly in both the subgranular zone and the granular cell layer of the dentate gyrus. In addition, Ahnak−/− mice displayed increased Doublecortin-immunoreactive neuroblasts compared with wild-type controls. Taken together, Ahnak deficiency plays a positive role for hippocampal neurogenesis in adult mice because proliferating cells were increased in Ahnak−/− mice and advanced to mature neurons. These findings suggest that Ahnak might be involved in modulating the differentiation of newly generated cells into neuronal or non-neuronal cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Masunaga T, Shimizu H, Ishiko A, Fujiwara T, Hashimoto T, Nishikawa T (1995) Desmoyokin/AHNAK protein localizes to the non-desmosomal keratinocyte cell surface of human epidermis. J Invest Dermatol 104(6):941–945

    Article  CAS  PubMed  Google Scholar 

  2. Shtivelman E, Cohen FE, Bishop JM (1992) A human gene (AHNAK) encoding an unusually large protein with a 1.2-microns polyionic rod structure. Proc Natl Acad Sci 89(12):5472–5476

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Ramirez-Amaya V, Marrone DF, Gage FH, Worley PF, Barnes CA (2006) Integration of new neurons into functional neural networks. J Neurosci 26(47):12237–12241

    Article  CAS  PubMed  Google Scholar 

  4. Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16(6):2027–2033

    CAS  PubMed  Google Scholar 

  5. Lee IH, Sohn M, Lim HJ, Yoon S, Oh H, Shin S, Shin JH, Oh SH, Kim J, Lee DK, Noh DY, Bae DS, Seong JK, Bae YS (2014) Ahnak functions as a tumor suppressor via modulation of TGF[beta]/Smad signaling pathway. Oncogene 33(38):4675–4684. doi:10.1038/onc.2014.69

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Lee IH, Lim HJ, Yoon S, Seong JK, Bae DS, Rhee SG, Bae YS (2008) Ahnak protein activates protein kinase C (PKC) through dissociation of the PKC-protein phosphatase 2A complex. J Biol Chem 283(10):6312–6320. doi:10.1074/jbc.M706878200 M706878200 [pii]

    Article  CAS  PubMed  Google Scholar 

  7. Paxinos G, Franklin KB (2004) The mouse brain in stereotaxic coordinates. Gulf Professional Publishing, Houston

    Google Scholar 

  8. Ming G-l, Song H (2005) Adult neurogenesis in the mammalian central nervous system. Annu Rev Neurosci 28:223–250

    Article  CAS  PubMed  Google Scholar 

  9. Kempermann G, Jessberger S, Steiner B, Kronenberg G (2004) Milestones of neuronal development in the adult hippocampus. Trends Neurosci 27(8):447–452

    Article  CAS  PubMed  Google Scholar 

  10. Mullen RJ, Buck CR, Smith AM (1992) NeuN, a neuronal specific nuclear protein in vertebrates. Development 116(1):201–211

    CAS  PubMed  Google Scholar 

  11. Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, Greenberg DA (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci 98(8):4710–4715

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Abrous DN, Koehl M, Le Moal M (2005) Adult neurogenesis: from precursors to network and physiology. Physiol Rev 85(2):523–569. doi:10.1152/physrev.00055.2003

    Article  CAS  PubMed  Google Scholar 

  13. Perera TD, Lu D, Thirumangalakudi L, Smith EL, Yaretskiy A, Rosenblum LA, Kral JG, Coplan JD (2011) Correlations between hippocampal neurogenesis and metabolic indices in adult nonhuman primates. Neural Plast 2011:1–6. doi:10.1155/2011/875307

  14. Kokoeva MV, Yin H, Flier JS (2005) Neurogenesis in the hypothalamus of adult mice: potential role in energy balance. Science 310(5748):679–683

    Article  CAS  PubMed  Google Scholar 

  15. Lindqvist A, Mohapel P, Bouter B, Frielingsdorf H, Pizzo D, Brundin P, Erlanson-Albertsson C (2006) High-fat diet impairs hippocampal neurogenesis in male rats. Eur J Neurol 13(12):1385–1388. doi:10.1111/j.1468-1331.2006.01500.x

    Article  CAS  PubMed  Google Scholar 

  16. Brown JP, Couillard-Després S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG (2003) Transient expression of doublecortin during adult neurogenesis. J Comp Neurol 467(1):1–10

    Article  CAS  PubMed  Google Scholar 

  17. Francis F, Koulakoff A, Boucher D, Chafey P, Schaar B, Vinet M-C, Friocourt G, McDonnell N, Reiner O, Kahn A (1999) Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating and differentiating neurons. Neuron 23(2):247–256

    Article  CAS  PubMed  Google Scholar 

  18. Gentil BJ, Benaud C, Delphin C, Remy C, Berezowski V, Cecchelli R, Feraud O, Vittet D, Baudier J (2005) Specific AHNAK expression in brain endothelial cells with barrier properties. J Cell Physiol 203(2):362–371

    Article  CAS  PubMed  Google Scholar 

  19. Boveri M, Kinsner A, Berezowski V, Lenfant A-M, Draing C, Cecchelli R, Dehouck M-P, Hartung T, Prieto P, Bal-Price A (2006) Highly purified lipoteichoic acid from gram-positive bacteria induces in vitro blood–brain barrier disruption through glia activation: role of pro-inflammatory cytokines and nitric oxide. Neuroscience 137(4):1193–1209

    Article  CAS  PubMed  Google Scholar 

  20. Salim C, Boxberg YV, Alterio J, Féréol S, Nothias F (2009) The giant protein AHNAK involved in morphogenesis and laminin substrate adhesion of myelinating Schwann cells. Glia 57(5):535–549. doi:10.1002/glia.20782

    Article  PubMed  Google Scholar 

  21. Downs K, McHugh J, Copp A, Shtivelman E (2002) Multiple developmental roles of Ahnak are suggested by localization to sites of placentation and neural plate fusion in the mouse conceptus. Mech Dev 119:31–38

    Article  Google Scholar 

  22. Kouno M, Kondoh G, Horie K, Komazawa N, Ishii N, Takahashi Y, Takeda J, Hashimoto T (2004) Ahnak/desmoyokin is dispensable for proliferation, differentiation, and maintenance of integrity in mouse epidermis. J Investig Dermatol 123(4):700–707

    Article  CAS  PubMed  Google Scholar 

  23. Hashimoto T, Amagai M, Parry D, Dixon TW, Tsukita S, Miki K, Sakai K, Inokuchi Y, Kudoh J (1993) Desmoyokin, a 680 kDa keratinocyte plasma membrane-associated protein, is homologous to the protein encoded by human gene AHNAK. J Cell Sci 105(2):275–286

    CAS  PubMed  Google Scholar 

  24. Sussman J, Stokoe D, Ossina N, Shtivelman E (2001) Protein kinase B phosphorylates AHNAK and regulates its subcellular localization. J Cell Biol 154(5):1019–1030

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Gentil BJ, Delphin C, Mbele GO, Deloulme JC, Ferro M, Garin J, Baudier J (2001) The Giant Protein AHNAK Is a Specific Target for the Calcium-and Zinc-binding S100B Protein POTENTIAL IMPLICATIONS FOR Ca2+ HOMEOSTASIS REGULATION BY S100B. J Biol Chem 276(26):23253–23261

    Article  CAS  PubMed  Google Scholar 

  26. Sorci G, Bianchi R, Riuzzi F, Tubaro C, Arcuri C, Giambanco I, Donato R (2010) S100B protein, a damage-associated molecular pattern protein in the brain and heart, and beyond. Cardiovasc Psychiatry Neurol 2010:656481. doi:10.1155/2010/656481

  27. Petrova TV, Hu J, Van Eldik LJ (2000) Modulation of glial activation by astrocyte-derived protein S100B: differential responses of astrocyte and microglial cultures. Brain Res 853(1):74–80

    Article  CAS  PubMed  Google Scholar 

  28. Nishiyama H, Knöpfel T, Endo S, Itohara S (2002) Glial protein S100B modulates long-term neuronal synaptic plasticity. Proc Natl Acad Sci 99(6):4037–4042. doi:10.1073/pnas.052020999

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grant from by National Research Foundation (NRF), which is funded by the Korean government (MEST) (20120008875) to Prof. Je Kyung Seong. This study was also supported by Soonchunhyang University Research Fund to Prof. Sun Shin Yi.

Author information

Authors and Affiliations

  1. Laboratory of Developmental Biology and Genomics, BK21 Program for Veterinary Science, Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul, 151-742, South Korea

    Jae Hoon Shin, Yo Na Kim, Il Yong Kim & Je Kyung Seong

  2. Korea Mouse Phenotyping Center (KMPC), Seoul National University, Seoul, 151-742, South Korea

    Jae Hoon Shin, Yo Na Kim, Il Yong Kim & Je Kyung Seong

  3. Research and Development Team, GyeongGi Bio-Center, Gyeonggi Institute of Science and Technology Promotion, Suwon, 443-270, South Korea

    Dong-Hwa Choi

  4. Department of Biomedical Laboratory Science, College of Biomedical Sciences, Soonchunhyang University, Asan, 336-745, South Korea

    Sun Shin Yi

Authors
  1. Jae Hoon Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yo Na Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Il Yong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong-Hwa Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sun Shin Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Je Kyung Seong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Sun Shin Yi or Je Kyung Seong.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shin, J.H., Kim, Y.N., Kim, I.Y. et al. Increased Cell Proliferations and Neurogenesis in the Hippocampal Dentate Gyrus of Ahnak Deficient Mice. Neurochem Res 40, 1457–1462 (2015). https://doi.org/10.1007/s11064-015-1615-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1615-0

Keywords

Search

Navigation