Skip to main content
SpringerLink
Log in

Activating transcription factor 5 (ATF5) is essential for the maturation and survival of mouse basal vomeronasal sensory neurons

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Activating transcription factor 5 (ATF5) is a member of the CREB/ATF family of transcription factors, which is highly expressed in olfactory chemosensory tissues, the main olfactory epithelium and vomeronasal epithelium (VNE) in mice. The vomeronasal sensory neurons in the VNE detect pheromones in order to regulate social behaviors such as mating and aggression; however, the physiological role of ATF5 in the vomeronasal sensory system remains unknown. In this study, we found that the differentiation of mature vomeronasal sensory neurons, assessed by olfactory marker protein expression, was inhibited in ATF5-deficient VNE. In addition, many apoptotic vomeronasal sensory neurons were evident in ATF5-deficient VNE. The vomeronasal sensory neurons consist of two major types of neuron expressing either vomeronasal 1 receptor (V1r)/Gαi2 or vomeronasal 2 receptor (V2r)/Gαo. We demonstrated that the differentiation, survival and axonal projection of V2r/Gαo-type rather than V1r/Gαi2-type vomeronasal sensory neurons were severely inhibited in ATF5-deficient VNE. These results suggest that ATF5 is one of the transcription factors crucial for the vomeronasal sensory formation.

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
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Belluscio L, Gold GH, Nemes A, Axel R (1998) Mice deficient in G(olf) are anosmic. Neuron 20:69–81

    Article  CAS  PubMed  Google Scholar 

  • Berghard A, Buck LB (1996) Sensory transduction in vomeronasal neurons: evidence for G alpha o, G alpha i2, and adenylyl cyclase II as major components of a pheromone signaling cascade. J Neurosci 16:909–918

    CAS  PubMed  Google Scholar 

  • Boschat C, Pelofi C, Randin O, Roppolo D, Luscher C, Broillet MC, Rodriguez I (2002) Pheromone detection mediated by a V1r vomeronasal receptor. Nat Neurosci 5:1261–1262

    Article  CAS  PubMed  Google Scholar 

  • Brann JH, Firestein S (2010) Regeneration of new neurons is preserved in aged vomeronasal epithelia. J Neurosci 30:15686–15694

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cau E, Gradwohl G, Fode C, Guillemot F (1997) Mash1 activates a cascade of bHLH regulators in olfactory neuron progenitors. Development 124:1611–1621

    CAS  PubMed  Google Scholar 

  • Chamero P, Katsoulidou V, Hendrix P, Bufe B, Roberts R, Matsunami H, Abramowitz J, Birnbaumer L, Zufall F, Leinders-Zufall T (2011) G protein G(alpha)o is essential for vomeronasal function and aggressive behavior in mice. Proc Natl Acad Sci U S A 108:12898–12903

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cloutier JF, Giger RJ, Koentges G, Dulac C, Kolodkin AL, Ginty DD (2002) Neuropilin-2 mediates axonal fasciculation, zonal segregation, but not axonal convergence, of primary accessory olfactory neurons. Neuron 33:877–892

    Article  CAS  PubMed  Google Scholar 

  • Dalton RP, Lyons DB, Lomvardas S (2013) Co-opting the unfolded protein response to elicit olfactory receptor feedback. Cell 155:321–332

    Article  CAS  PubMed  Google Scholar 

  • Dey S, Matsunami H (2011) Calreticulin chaperones regulate functional expression of vomeronasal type 2 pheromone receptors. Proc Natl Acad Sci U S A 108:16651–16656

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Dluzen D, Li G, Tacelosky D, Moreau M, Liu DX (2011) BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner. J Biol Chem 286:7705–7713

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Eckler MJ, McKenna WL, Taghvaei S, McConnell SK, Chen B (2011) Fezf1 and Fezf2 are required for olfactory development and sensory neuron identity. J Comp Neurol 519:1829–1846

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Enomoto T, Ohmoto M, Iwata T, Uno A, Saitou M, Yamaguchi T, Kominami R, Matsumoto I, Hirota J (2011) Bcl11b/Ctip2 controls the differentiation of vomeronasal sensory neurons in mice. J Neurosci 31:10159–10173

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ferrero DM, Moeller LM, Osakada T, Horio N, Li Q, Roy DS, Cichy A, Spehr M, Touhara K, Liberles SD (2013) A juvenile mouse pheromone inhibits sexual behaviour through the vomeronasal system. Nature 502:368–371

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Haga S, Hattori T, Sato T, Sato K, Matsuda S, Kobayakawa R, Sakano H, Yoshihara Y, Kikusui T, Touhara K (2010) The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor. Nature 466:118–122

    Article  CAS  PubMed  Google Scholar 

  • Hansen MB, Mitchelmore C, Kjaerulff KM, Rasmussen TE, Pedersen KM, Jensen NA (2002) Mouse Atf5: molecular cloning of two novel mRNAs, genomic organization, and odorant sensory neuron localization. Genomics 80:344–350

    Article  CAS  PubMed  Google Scholar 

  • Hatano M, Umemura M, Kimura N, Yamazaki T, Takeda H, Nakano H, Takahashi S, Takahashi Y (2013) The 5′-untranslated region regulates ATF5 mRNA stability via nonsense-mediated mRNA decay in response to environmental stress. FEBS J 280:4693–4707

    Article  CAS  PubMed  Google Scholar 

  • Herrada G, Dulac C (1997) A novel family of putative pheromone receptors in mammals with a topographically organized and sexually dimorphic distribution. Cell 90:763–773

    Article  CAS  PubMed  Google Scholar 

  • Hornberg M, Gussing F, Berghard A, Bohm S (2009) Retinoic acid selectively inhibits death of basal vomeronasal neurons during late stage of neural circuit formation. J Neurochem 110:1265–1275

    Article  Google Scholar 

  • Isogai Y, Si S, Pont-Lezica L, Tan T, Kapoor V, Murthy VN, Dulac C (2011) Molecular organization of vomeronasal chemoreception. Nature 478:241–245

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jia C, Halpern M (1996) Subclasses of vomeronasal receptor neurons: differential expression of G proteins (Gi alpha 2 and G(o alpha)) and segregated projections to the accessory olfactory bulb. Brain Res 719:117–128

    Article  CAS  PubMed  Google Scholar 

  • Kaur AW, Ackels T, Kuo TH, Cichy A, Dey S, Hays C, Kateri M, Logan DW, Marton TF, Spehr M, Stowers L (2014) Murine pheromone proteins constitute a context-dependent combinatorial code governing multiple social behaviors. Cell 157:676–688

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Leinders-Zufall T, Brennan P, Widmayer P, Shivalingappa PC, Maul-Pavicic A, Jager M, Li XH, Breer H, Zufall F, Boehm T (2004) MHC class I peptides as chemosensory signals in the vomeronasal organ. Science 306:1033–1037

  • Liberles SD (2014) Mammalian pheromones. Annu Rev Physiol 76:151–175

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mandiyan VS, Coats JK, Shah NM (2005) Deficits in sexual and aggressive behaviors in Cnga2 mutant mice. Nat Neurosci 8:1660–1662

    Article  CAS  PubMed  Google Scholar 

  • Matsunami H, Buck LB (1997) A multigene family encoding a diverse array of putative pheromone receptors in mammals. Cell 90:775–784

    Article  CAS  PubMed  Google Scholar 

  • Matsuo T, Hattori T, Asaba A, Inoue N, Kanomata N, Kikusui T, Kobayakawa R, Kobayakawa K (2015) Genetic dissection of pheromone processing reveals main olfactory system-mediated social behaviors in mice. Proc Natl Acad Sci U S A 112:E311–E320

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Montani G, Tonelli S, Sanghez V, Ferrari PF, Palanza P, Zimmer A, Tirindelli R (2013) Aggressive behaviour and physiological responses to pheromones are strongly impaired in mice deficient for the olfactory G-protein -subunit G8. J Physiol 591:3949–3962

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Murray RC, Navi D, Fesenko J, Lander AD, Calof AL (2003) Widespread defects in the primary olfactory pathway caused by loss of Mash1 function. J Neurosci 23:1769–1780

    CAS  PubMed  Google Scholar 

  • Norlin EM, Gussing F, Berghard A (2003) Vomeronasal phenotype and behavioral alterations in Gαi2 mutant mice. Curr Biol 13:1214–1219

    Article  CAS  PubMed  Google Scholar 

  • Perez-Gomez A, Stein B, Leinders-Zufall T, Chamero P (2014) Signaling mechanisms and behavioral function of the mouse basal vomeronasal neuroepithelium. Front Neuroanat 8:135

    PubMed Central  PubMed  Google Scholar 

  • Prince JE, Brignall AC, Cutforth T, Shen K, Cloutier JF (2013) Kirrel3 is required for the coalescence of vomeronasal sensory neuron axons into glomeruli and for male-male aggression. Development 140:2398–2408

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Riviere S, Challet L, Fluegge D, Spehr M, Rodriguez I (2009) Formyl peptide receptor-like proteins are a novel family of vomeronasal chemosensors. Nature 459:574–577

    Article  CAS  PubMed  Google Scholar 

  • Ryba NJ, Tirindelli R (1997) A new multigene family of putative pheromone receptors. Neuron 19:371–379

    Article  CAS  PubMed  Google Scholar 

  • Shimizu YI, Morita M, Ohmi A, Aoyagi S, Ebihara H, Tonaki D, Horino Y, Iijima M, Hirose H, Takahashi S, Takahashi Y (2009) Fasting induced up-regulation of activating transcription factor 5 in mouse liver. Life Sci 84:894–902

    Article  CAS  PubMed  Google Scholar 

  • Simmons DG, Natale DR, Begay V, Hughes M, Leutz A, Cross JC (2008) Early patterning of the chorion leads to the trilaminar trophoblast cell structure in the placental labyrinth. Development 135:2083–2091

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stowers L, Holy TE, Meister M, Dulac C, Koentges G (2002) Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science 295:1493–1500

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Treloar H, Kalb RG, Greer CA, Strittmatter SM (1999) G(o) protein-dependent survival of primary accessory olfactory neurons. Proc Natl Acad Sci U S A 96:14106–14111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Umemura M, Tsunematsu K, Shimizu YI, Nakano H, Takahashi S, Higashiura Y, Okabe M, Takahashi Y (2015) Activating transcription factor 5 is required for mouse olfactory bulb development via interneuron. Biosci Biotechnol Biochem 79:1082–1089

    Article  CAS  PubMed  Google Scholar 

  • Wang Z, Sindreu CB, Li V, Nudelman A, Chan GCK, Daniel R, Storm DR (2006) Pheromone detection in male mice depends on signaling through the type 3 adenylyl cyclase in the main olfactory epithelium. J Neurosci 26:7375–7379

    Article  CAS  PubMed  Google Scholar 

  • Wang SZ, Ou J, Zhu LJ, Green MR (2012) Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. Proc Natl Acad Sci U S A 109:18589–18594

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Watatani Y, Ichikawa K, Nakanishi N, Fujimoto M, Takeda H, Kimura N, Hirose H, Takahashi S, Takahashi Y (2008) Stress-induced translation of ATF5 mRNA is regulated by the 5′-untranslated region. J Biol Chem 283:2543–2553

    Article  CAS  PubMed  Google Scholar 

  • Watt WC, Sakano H, Lee ZY, Reusch JE, Trinh K, Storm DR (2004) Odorant stimulation enhances survival of olfactory sensory neurons via MAPK and CREB. Neuron 41:955–967

    Article  CAS  PubMed  Google Scholar 

  • Wong ST, Trinh K, Hacker B, Chan GC, Lowe G, Gaggar A, Xia Z, Gold GH, Storm DR (2000) Disruption of the type III adenylyl cyclase gene leads to peripheral and behavioral anosmia in transgenic mice. Neuron 27:487–497

    Article  CAS  PubMed  Google Scholar 

  • Zhou D, Palam LR, Jiang L, Narasimhan J, Staschke KA, Wek RC (2008) Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J Biol Chem 283:7064–7073

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations

  1. Laboratory of Environmental Molecular Physiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Haruo Nakano, Yoshitaka Iida, Makoto Suzuki, Marie Aoki, Mariko Umemura, Shigeru Takahashi & Yuji Takahashi

Authors
  1. Haruo Nakano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshitaka Iida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Makoto Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marie Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariko Umemura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shigeru Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuji Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yuji Takahashi.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Suppl Fig. S1

Double immunofluorescence with anti-OMP and anti- Gαi2 for AOB imaging analysis. Double immunofluorescence of OMP (a, b) and Gαi2 (c, d) with the merge image (e, f) on adult ATF5+/+ and ATF5-/- accessory olfactory bulb (AOB). A and P indicate anterior and posterior direction, respectively. The dotted line delineates the region of vomeronasal nerve layer and glomerular layer (vnl-gl) of the AOB. Arrowheads indicate the border between the anterior and posterior region of the AOB. Scale bars 100 μm. (GIF 27 kb)

High resolution image (TIFF 4883 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nakano, H., Iida, Y., Suzuki, M. et al. Activating transcription factor 5 (ATF5) is essential for the maturation and survival of mouse basal vomeronasal sensory neurons. Cell Tissue Res 363, 621–633 (2016). https://doi.org/10.1007/s00441-015-2283-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-015-2283-8

Keywords

Search

Navigation