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Co-expression of C/EBPγ and ATF5 in mouse vomeronasal sensory neurons during early postnatal development

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Abstract

The differentiation of sensory neurons involves gene expression changes induced by specific transcription factors. Vomeronasal sensory neurons (VSNs) in the mouse vomeronasal organ (VNO) consist of two major subpopulations of neurons expressing vomeronasal 1 receptor (V1r)/Gαi2 or vomeronasal 2 receptor (V2r)/Gαo, which differentiate from a common neural progenitor. We previously demonstrated that the differentiation and survival of VSNs were inhibited in ATF5 transcription factor-deficient mice (Nakano et al. Cell Tissue Res 363:621–633, 2016). These defects were more prominent in V2r/Gαo-type than in V1r/Gαi2-type VSNs; however, the molecular mechanisms responsible for the differentiation of V2r/Gαo-type VSNs by ATF5 remain unclear. To identify a cofactor involved in ATF5-regulated VSN differentiation, we investigated the expression and function of CCAAT/enhancer-binding protein gamma (C/EBPγ, Cebpg), which is a major C/EBP family member expressed in the mouse VNO and dimerizes with ATF5. The results obtained showed that C/EBPγ mRNAs and proteins were broadly expressed in the postmitotic VSNs of the neonatal VNO, and their expression decreased by the second postnatal week. The C/EBPγ protein was expressed in the nuclei of approximately 70% of VSNs in the neonatal VNO, and 20% of the total VSNs co-expressed C/EBPγ and ATF5 proteins. We examined the trans-acting effects of C/EBPγ and ATF5 on V2r transcription and found that the co-expression of C/EBPγ and ATF5, but not C/EBPγ or ATF5 alone, increased Vmn2r66 promoter reporter activity via the C/EBP:ATF response element (CARE) in Neuro2a cells. These results suggest the role of C/EBPγ on ATF5-regulated VSN differentiation in early postnatal development.

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References

  • Barber PC, Raisman G (1978) Cell division in the vomeronasal organ of the adult mouse. Brain Res 141:57–66

    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  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  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 

  • Chang I, Parrilla M (2016) Expression patterns of homeobox genes in the mouse vomeronasal organ at postnatal stages. Gene Expr Patterns 21:69–80

    CAS  PubMed  Google Scholar 

  • Cooper C, Henderson A, Artandi S, Avitahl N, Calame K (1995) Ig/EBP (C/EBPγ) is a transdominant negative inhibitor of C/EBP family transcriptional activators. Nucleic Acids Res 23:4371–4377

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cuschieri A, Bannister LH (1975) The development of the olfactory mucosa in the mouse: light microscopy. J Anat 119:277–286

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dalton RP (2018) Shared genetic requirements for ATF5 translation in the vomeronasal organ and main olfactory epithelium [version 1; referees: awaiting peer review]. F1000Research 7:73. https://doi.org/10.12688/f1000research.13659.1)

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • De La Rosa-Prieto C, Saiz-Sanchez D, Ubeda-Banon I, Argandona-Palacios L, Garcia-Munozguren S, Martinez-Marcos A (2010) Neurogenesis in subclasses of vomeronasal sensory neurons in adult mice. Dev Neurobiol 70:961–970

    PubMed  Google Scholar 

  • Dulac C, Axel R (1995) A novel family of genes encoding putative pheromone receptors in mammals. Cell 83:195–206

    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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Garrosa M, Coca S (1991) Postnatal development of the vomeronasal epithelium in rat: an ultrastructural study. J Morphol 208:257–269

    CAS  PubMed  Google Scholar 

  • Giacobini P, Benedetto A, Tirindelli R, Fasolo A (2000) Proliferation and migration of receptor neurons in the vomeronasal organ of the adult mouse. Dev Brain Res 123:33–40

    CAS  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

    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

    CAS  PubMed  Google Scholar 

  • Huggins CJ, Mayekar MK, Martin N, Saylor KL, Gonit M, Jailwala P, Kasoji M, Haines DC, Quinones OA, Johnson PF (2016) C/EBPγ is a critical regulator of cellular stress response networks through heterodimerization with ATF4. Mol Cell Biol 36:693–713

    CAS  PubMed Central  Google Scholar 

  • Ibarra-Soria X, Levitin MO, Saraiva LR, Logan DW (2014) The olfactory transcriptomes of mice. PLoS Genet 10:e1004593

    PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Juliana CA, Yang J, Rozo AV, Good A, Groff DN, Wang SZ, Green MR, Stoffers DA (2017) ATF5 regulates β-cell survival during stress. Proc Natl Acad Sci U S A 114:1341–1346

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kaisho T, Tsutsui H, Tanaka T, Tsujimura T, Takeda K, Kawai T, Yoshida N, Nakanishi K, Akira S (1999) Impairment of natural killer cytotoxic activity and interferon gamma production in CCAAT/enhancer binding protein gamma-deficient mice. J Exp Med 190:1573–1582

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khan A, Fornes O, Stigliani A, Gheorghe M, Castro-Mondragon JA, van der Lee R, Bessy A, Cheneby J, Kulkarni SR, Tan G, Baranasic D, Arenillas DJ, Sandelin A, Vandepoele K, Lenhard B, Ballester B, Wasserman WW, Parcy F, Mathelier A (2018) JASPAR 2018: update of the open-access database of transcription factor binding profiles and its web framework. Nucleic Acids Res 46:D260–D266

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Lin JM, Taroc EZM, Frias JA, Prasad A, Catizone AN, Sammons MA, Forni PE (2018) The transcription factor Tfap2e/AP-2ε plays a pivotal role in maintaining the identity of basal vomeronasal sensory neurons. Dev Biol 441:67–82

    CAS  PubMed  Google Scholar 

  • Martinez-Marcos A, Jia C, Quan W, Halpern M (2005) Neurogenesis, migration, and apoptosis in the vomeronasal epithelium of adult mice. J Neurobiol 63:173–187

    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

    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  PubMed Central  Google Scholar 

  • Nakano H, Iida Y, Suzuki M, Aoki M, Umemura M, Takahashi S, Takahashi Y (2016) Activating transcription factor 5 (ATF5) is essential for the maturation and survival of mouse basal vomeronasal sensory neurons. Cell Tissue Res 363:621–633

    CAS  PubMed  Google Scholar 

  • Newman JR, Keating AE (2003) Comprehensive identification of human bZIP interactions with coiled-coil arrays. Science 300:2097–2101

    CAS  PubMed  Google Scholar 

  • Nishizawa M, Nagata S (1992) cDNA clones encoding leucine-zipper proteins which interact with G-CSF gene promoter element 1-binding protein. FEBS Lett 299:36–38

    CAS  PubMed  Google Scholar 

  • Oboti L, Ibarra-Soria X, Perez-Gomez A, Schmid A, Pyrski M, Paschek N, Kircher S, Logan DW, Leinders-Zufall T, Zufall F, Chamero P (2015) Pregnancy and estrogen enhance neural progenitor-cell proliferation in the vomeronasal sensory epithelium. BMC Biol 13:104

    PubMed  PubMed Central  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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    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

    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

    CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki Y, Mizoguchi I, Nishiyama H, Takeda M, Obara N (2003) Expression of Hes6 and NeuroD in the olfactory epithelium, vomeronasal organ and non-sensory patches. Chem Senses 28:197–205

    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

    CAS  PubMed  Google Scholar 

  • Vinson CR, Hai T, Boyd SM (1993) Dimerization specificity of the leucine zipper-containing bZIP motif on DNA binding: prediction and rational design. Genes Dev 7:1047–1058

    CAS  PubMed  Google Scholar 

  • Wakabayashi Y, Ichikawa M (2007) Distribution of Notch1-expressing cells and proliferating cells in mouse vomeronasal organ. Neurosci Lett 411:217–221

    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

    CAS  PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

  • Weiler E, McCulloch MA, Farbman AI (1999) Proliferation in the vomeronasal organ of the rat during postnatal development. Eur J Neurosci 11:700–711

    CAS  PubMed  Google Scholar 

  • Zhao Y, Zhang YD, Zhang YY, Qian SW, Zhang ZC, Li SF, Guo L, Liu Y, Wen B, Lei QY, Tang QQ, Li X (2014) p300-dependent acetylation of activating transcription factor 5 enhances C/EBPβ transactivation of C/EBPα during 3T3-L1 differentiation. Mol Cell Biol 34:315–324

    PubMed  PubMed Central  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

    CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the members of the Takahashi laboratory for their support and useful discussions.

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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, Takahiro Murase, Natsuki Oyama, Mariko Umemura, Shigeru Takahashi & Yuji Takahashi

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  1. Haruo Nakano
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  2. Yoshitaka Iida
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  3. Takahiro Murase
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  4. Natsuki Oyama
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  6. Shigeru Takahashi
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  7. Yuji Takahashi
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Correspondence to Haruo Nakano.

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All mouse studies were approved by the Institutional Animal Experiment Committee of the university and were performed in accordance with institutional and governmental guidelines.

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Nakano, H., Iida, Y., Murase, T. et al. Co-expression of C/EBPγ and ATF5 in mouse vomeronasal sensory neurons during early postnatal development. Cell Tissue Res 378, 427–440 (2019). https://doi.org/10.1007/s00441-019-03070-2

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