Dimorphic Mechanism on cAMP Mediated Signal Pathway in Mucor circinelloides


Mucor circinelloides is a dimorphic fungus that is a non-pathogen strain belonging to zygomycetes. In this research, a part of hypothetical mechanism on yeast-like cell induction of M. circinelloides in CO2 atmosphere was reported from the viewpoint of gene expression. To explain the relation between the change and the expressions of some genes involved in morphological changes of the strain, these were analyzed on the filamentous and yeast cell by real-time qPCR. The compared genes were Nce103, Ras3, Cyr1, Pde, and Efg1 encoding carbonic anhydrase, GTPase, adenylate cyclase, phosphodiesterase, and elongation factor G1, respectively. In anaerobic grown yeast cell with 70%N2 + 30%CO2, the Nce103 and Ras3 gene expressions decreased to 24 h whereas that of the filamentous cell increased. However, a downstream gene of Cyr1 expression level in the yeast cell was higher than that of filamentous cell. A lower level of Pde in the yeast cell than that of the filamentous cell indicated intracellular cAMP accumulation. The actual cAMP in the yeast cell remained whereas that of the filamentous cell decreased with cultivation. The Efg1 expression level controlling hyphal elongation was suppressed in the yeast cell. The intracellular cAMP accumulation and Efg1 expression regulate hyphal elongation or yeast forming.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Data Availability

The datasets during and/or analyzed during the current study are available from the corresponding author on a reasonable request.


  1. 1.

    Orlowski, M. (1991). Mucor dimorphism, 55(2), 234–258.

  2. 2.

    McIntyre, M., Breum, J., Arnau, J., & Nielsen, J. (2002). Growth physiology and dimorphism of Mucor circinelloides (syn. racemosus) during submerged batch cultivation. Applied Microbiology and Biotechnology, 58(4), 495–502. https://doi.org/10.1007/s00253-001-0916-1.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Serrano, I., Lopes Da Silva, T., & Carlos Roseiro, J. (2001). Ethanol-induced dimorphism and lipid composition changes in Mucor fragilis CCMI 142. Letters in Applied Microbiology, 33(1), 89–93. https://doi.org/10.1046/j.1472-765X.2001.00958.x.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Wolff, A. M., Appel, K. F., Petersen, J. B., Poulsen, U., & Arnau, J. (2002). Identification and analysis of genes involved in the control of dimorphism in Mucor circinelloides (syn. racemosus). FEMS Yeast Research, 2(2), 203–213. https://doi.org/10.1016/S1567-1356(02)00090-9.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Whiteway, M., & Bachewich, C. (2007). Morphogenesis in Candida albicans. Annual Review of Microbiology, 61(1), 529–553. https://doi.org/10.1146/annurev.micro.61.080706.093341.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Edwards, J. A., Chen, C., Kemski, M. M., Hu, J., Mitchell, T. K., & Rappleye, C. A. (2013). Histoplasma yeast and mycelial transcriptomes reveal pathogenic-phase and lineage-specific gene expression profiles. BMC Genomics, 14(1), 695. https://doi.org/10.1186/1471-2164-14-695.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Gauthier, G. M. (2017). Fungal dimorphism and virulence: molecular mechanisms for temperature adaptation, immune evasion, and in vivo survival. Mediators of Inflammation, 2017, 1–8. https://doi.org/10.1155/2017/8491383.

    CAS  Article  Google Scholar 

  8. 8.

    Pomraning, K. R., Bredeweg, E. L., Kerkhoven, E. J., Barry, K., Haridas, S., Hundley, H., … Baker, S. E. (2018). Regulation of yeast-to-hyphae transition in Yarrowia lipolytica . mSphere, 3(6), 1–18. doi:https://doi.org/10.1128/msphere.00541-18.

  9. 9.

    Klein, B. S., & Tebbets, B. (2007). Dimorphism and virulence in fungi. Current Opinion in Microbiology, 10(4), 314–319. https://doi.org/10.1016/j.mib.2007.04.002.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Kim, J., & Sudbery, P. (2011). Candida albicans, a major human fungal pathogen. Journal of Microbiology, 49(2), 171–177. https://doi.org/10.1007/s12275-011-1064-7.

    Article  Google Scholar 

  11. 11.

    Kadosh, D. (2016). Control of Candida albicans morphology and pathogenicity by post-transcriptional mechanisms. Cellular and Molecular Life Sciences, 73(22), 4265–4278. https://doi.org/10.1007/s00018-016-2294-y.

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Ramírez-Quijas, M. D., Zazueta-Sandoval, R., Obregón-Herrera, A., López-Romero, E., & Cuéllar-Cruz, M. (2015). Effect of oxidative stress on cell wall morphology in four pathogenic Candida species. Mycological Progress, 14(3). https://doi.org/10.1007/s11557-015-1028-0.

  13. 13.

    Nascimento, T. P., Sales, A. E., Porto, C. S., Brandão, R. M. P., de Campos-Takaki, G. M., Teixeira, J. A. C., Porto, T. S., Porto, A. L. F., & Converti, A. (2016). Purification of a fibrinolytic protease from Mucor subtilissimus UCP 1262 by aqueous two-phase systems (PEG/sulfate). Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences, 1025, 16–24. https://doi.org/10.1016/j.jchromb.2016.04.046.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Carvalho, A. K. F., da Conceição, L. R. V., Silva, J. P. V., Perez, V. H., & de Castro, H. F. (2017). Biodiesel production from Mucor circinelloides using ethanol and heteropolyacid in one and two-step transesterification. Fuel, 202, 503–511. https://doi.org/10.1016/j.fuel.2017.04.063.

    CAS  Article  Google Scholar 

  15. 15.

    Molaverdi, M., Karimi, K., Mirmohamadsadeghi, S., & Galbe, M. (2019). High titer ethanol production from rice straw via solid-state simultaneous saccharification and fermentation by Mucor indicus at low enzyme loading. Energy Conversion and Management, 182(January), 520–529. https://doi.org/10.1016/j.enconman.2018.12.078.

    CAS  Article  Google Scholar 

  16. 16.

    Lennartsson, P. R., Karimi, K., Edebo, L., & Taherzadeh, M. J. (2009). Effects of different growth forms of Mucor indicus on cultivation on dilute-acid lignocellulosic hydrolyzate, inhibitor tolerance, and cell wall composition. Journal of Biotechnology, 143(4), 255–261. https://doi.org/10.1016/j.jbiotec.2009.07.011.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Dickman, M. B., & Yarden, O. (1999). Serine/threonine protein kinases and phosphatases in filamentous fungi. Fungal Genetics and Biology, 26(2), 99–117. https://doi.org/10.1006/fgbi.1999.1118.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Wendland, J. (2001). Comparison of morphogenetic networks of filamentous fungi and yeast. Fungal Genetics and Biology, 34(2), 63–82. https://doi.org/10.1006/fgbi.2001.1290.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Kubo, H., & Mihara, H. (2007). cAMP promotes hyphal branching in Mucor globosus. Mycoscience, 48(3), 187–189. https://doi.org/10.1007/s10267-007-0348-6.

    CAS  Article  Google Scholar 

  20. 20.

    Lindsay, A. K., Deveau, A., Piispanen, A. E., & Hogan, D. A. (2012). Farnesol and cyclic AMP signaling effects on the hypha-to-yeast transition in Candida albicans. Eukaryotic Cell, 11(10), 1219–1225. https://doi.org/10.1128/EC.00144-12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Parrino, S. M., Si, H., Naseem, S., Groudan, K., Gardin, J., & Konopka, J. B. (2017). cAMP-independent signal pathways stimulate hyphal morphogenesis in Candida albicans. Molecular Microbiology, 103(5), 764–779. https://doi.org/10.1111/mmi.13588.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Lübbehüsen, T. L., Nielsen, J., & McIntyre, M. (2003). Morphology and physiology of the dimorphic fungus Mucor circinelloides (syn. M. racemosus) during anaerobic growth. Mycological Research, 107(2), 223–230. https://doi.org/10.1017/S0953756203007299.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    BARTNICKI-GARCIA, S., & NICKERSON, W. J. (1962). Induction of yeast-like development in Mucor by carbon dioxide. Journal of Bacteriology, 84(4), 829–840.

    CAS  Article  Google Scholar 

  24. 24.

    Fernández Núñez, L., Ocampo, J., Gottlieb, A. M., Rossi, S., & Moreno, S. (2016). Multiple isoforms for the catalytic subunit of PKA in the basal fungal lineage Mucor circinelloides. Fungal Biology, 120(12), 1493–1508. https://doi.org/10.1016/j.funbio.2016.07.013.

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Klengel, T., Liang, W. J., Chaloupka, J., Ruoff, C., Schröppel, K., Naglik, J. R., Eckert, S. E., Mogensen, E. G., Haynes, K., Tuite, M. F., Levin, L. R., Buck, J., & Mühlschlegel, F. A. (2005). Fungal adenylyl cyclase integrates CO2 sensing with cAMP signaling and virulence. Current Biology, 15(22), 2021–2026. https://doi.org/10.1016/j.cub.2005.10.040.

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Valle-Maldonado, M. I., Jácome-Galarza, I. E., Gutiérrez-Corona, F., Ramírez-Díaz, M. I., Campos-García, J., & Meza-Carmen, V. (2015). Selection of reference genes for quantitative real time RT-PCR during dimorphism in the zygomycete Mucor circinelloides. Molecular Biology Reports, 42(3), 705–711. https://doi.org/10.1007/s11033-014-3818-x.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Liu, H. (2002). Co-regulation of pathogenesis with dimorphism and phenotypic switching in Candida albicans, a commensal and a pathogen. International Journal of Medical Microbiology, 292(5–6), 299–311. https://doi.org/10.1078/1438-4221-00215.

    CAS  Article  PubMed  Google Scholar 

  28. 28.

    Komeda, H., Yamasaki-Yashiki, S., Hoshino, K., & Asano, Y. (2014). Identification and characterization of D-xylulokinase from the D-xylose-fermenting fungus, Mucor circinelloides. FEMS Microbiology Letters, 360(1), 51–61. https://doi.org/10.1111/1574-6968.12589.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Takano, M., & Hoshino, K. (2018). Bioethanol production from rice straw by simultaneous saccharification and fermentation with statistical optimized cellulase cocktail and fermenting fungus. Bioresources and Bioprocessing, 5(1). https://doi.org/10.1186/s40643-018-0203-y.

  30. 30.

    Mizoguchi, H., & Hara, S. (1996). Effect of fatty acid saturation in membrane lipid bilayers on simple diffusion in the presence of ethanol at high concentrations. Journal of Fermentation and Bioengineering, 81(5), 406–411. https://doi.org/10.1016/0922-338X(96)85141-5.

    CAS  Article  Google Scholar 

  31. 31.

    Feng, Q., Summers, E., Guo, B., & Fink, G. (1999). Ras signaling is required for serum-induced hyphal differentiation in Candida albicans. Journal of Bacteriology, 181(20), 6339–6346.

    CAS  Article  Google Scholar 

  32. 32.

    Fang, H. M., & Wang, Y. (2006). RA domain-mediated interaction of Cdc35 with Ras3 is essential for increasing cellular cAMP level for Candida albicans hyphal development. Molecular Microbiology, 61(2), 484–496. https://doi.org/10.1111/j.1365-2958.2006.05248.x.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Zou, H., Fang, H. M., Zhu, Y., & Wang, Y. (2010). Candida albicans Cyr1, Cap1 and G-actin form a sensor/effector apparatus for activating cAMP synthesis in hyphal growth. Molecular Microbiology, 75(3), 579–591. https://doi.org/10.1111/j.1365-2958.2009.06980.x.

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Saito, H., Tamura, M., Imai, K., Ishigami, T., & Ochiai, K. (2013). Catechin inhibits Candida albicans dimorphism by disrupting Cek1 phosphorylation and cAMP synthesis. Microbial Pathogenesis, 56, 16–20. https://doi.org/10.1016/j.micpath.2013.01.002.

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    Lee, S.-M., Jellison, T., & Alper, H. S. (2014). Systematic and evolutionary engineering of a xylose isomerase-based pathway in Saccharomyces cerevisiae for efficient conversion yields. Biotechnology for Biofuels, 7(1), 122. https://doi.org/10.1186/s13068-014-0122-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Ocampo, J., McCormack, B., Navarro, E., Moreno, S., Garre, V., & Rossi, S. (2012). Protein kinase a regulatory subunit isoforms regulate growth and differentiation in Mucor circinelloides: essential role of pkaR4. Eukaryotic Cell, 11(8), 989–1002. https://doi.org/10.1128/EC.00017-12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Sohn, K., Urban, C., Brunner, H., & Rupp, S. (2003). EFG1 is a major regulator of cell wall dynamics in Candida albicans as revealed by DNA microarrays. Molecular Microbiology, 47(1), 89–102. https://doi.org/10.1046/j.1365-2958.2003.03300.x.

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Leija, A., Ruiz-Herrera, J., & Mora, J. (1986). Effect of L-amino acids on Mucor rouxii dimorphism. Journal of Bacteriology, 168(2), 843–850. https://doi.org/10.1128/jb.168.2.843-850.1986.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Kazuhiro Hoshino.

Ethics declarations

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

Ethical approval and consent to participate do not apply.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

The presenting author of this manuscript in ACB2019 is Maki Moriwaki-Takano.

The title of the presentation is “Elucidation of dimorphic mechanism on cAMP mediated signal pathway in Mucor circinelloides” as P1-036.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Moriwaki-Takano, M., Iwakura, R. & Hoshino, K. Dimorphic Mechanism on cAMP Mediated Signal Pathway in Mucor circinelloides. Appl Biochem Biotechnol 193, 1252–1265 (2021). https://doi.org/10.1007/s12010-020-03342-6

Download citation


  • Fungal dimorphism
  • Morphology
  • CO2
  • cAMP
  • Elongation factor G1
  • Mucor circinelloides