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Effects of Maternal Marginal Iodine Deficiency on Dendritic Morphology in the Hippocampal CA1 Pyramidal Neurons in Rat Offspring

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Abstract

Although the salt iodization programmes are taken to control iodine deficiency (ID), some regions are still suffering from marginal ID. During pregnancy, marginal ID frequently leads to subtle insufficiency of thyroid hormones, characterized as low serum T4 levels. Therefore, the present research was to explore the effects of maternal marginal ID exposure on dendritic arbor growth in the hippocampal CA1 region and the underlying mechanisms. We established Wistar rat models with ID diet during pregnancy and lactation. The overall daily iodine intakes of the rats were estimated as 7.0, 5.0 and 1.5 μg/day in the control, marginal ID and severe ID groups, respectively. To study the morphological alterations of pyramidal neurons, Golgi–Cox procedure was conducted in the hippocampus. Sholl analyses demonstrated a slight decrease in the total length and branching numbers of basal dendrites on postnatal day (PN) 7, PN14 and PN21 in marginal ID group relative to the controls. However, there was no overt morphological change observed in apical dendrites. Immunofluorescence and Western blot analysis indicated that phosphorylation of MAP2, stathmin and JNK1 was down-regulated in marginal ID group. We speculate that the pups treated with maternal marginal ID subjected to subtle changes in dendritic growth of CA1 pyramidal neurons, which may be associated with the dysregulation of MAP2 and stathmin in a JNK1-dependent manner.

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References

  • Berling, B., Wille, H., Roll, B., Mandelkow, E. M., Garner, C., & Mandelkow, E. (1994). Phosphorylation of microtubule-associated proteins MAP2a, b and MAP2c at Ser136 by proline-directed kinases in vivo and in vitro. European Journal of Cell Biology, 64(1), 120–130.

    CAS  PubMed  Google Scholar 

  • Bjorkblom, B., Ostman, N., Hongisto, V., Komarovski, V., Filen, J. J., Nyman, T. A., et al. (2005). Constitutively active cytoplasmic c-Jun N-terminal kinase 1 is a dominant regulator of dendritic architecture: Role of microtubule-associated protein 2 as an effector. Journal of Neuroscience, 25(27), 6350–6361.

    Article  PubMed  Google Scholar 

  • Brent, G. A. (1994). The molecular basis of thyroid hormone action. New England Journal of Medicine, 331(13), 847–853.

    Article  CAS  PubMed  Google Scholar 

  • Cassimeris, L. (2002). The oncoprotein 18/stathmin family of microtubule destabilizers. Current Opinion in Cell Biology, 14(1), 18–24.

    Article  CAS  PubMed  Google Scholar 

  • Chang, L., Jones, Y., Ellisman, M. H., Goldstein, L. S., & Karin, M. (2003). JNK1 is required for maintenance of neuronal microtubules and controls phosphorylation of microtubule-associated proteins. Developmental Cell, 4(4), 521–533.

    Article  CAS  PubMed  Google Scholar 

  • Charbaut, E., Curmi, P. A., Ozon, S., Lachkar, S., Redeker, V., & Sobel, A. (2001). Stathmin family proteins display specific molecular and tubulin binding properties. Journal of Biological Chemistry, 276(19), 16146–16154.

    Article  CAS  PubMed  Google Scholar 

  • Ciani, L., & Salinas, P. C. (2007). c-Jun N-terminal kinase (JNK) cooperates with Gsk3beta to regulate Dishevelled-mediated microtubule stability. BMC Cell Biology, 8, 27.

    Article  PubMed  PubMed Central  Google Scholar 

  • Conde, C., & Caceres, A. (2009). Microtubule assembly, organization and dynamics in axons and dendrites. Nature Reviews Neuroscience, 10(5), 319–332.

    Article  CAS  PubMed  Google Scholar 

  • Dehmelt, L., & Halpain, S. (2005). The MAP2/Tau family of microtubule-associated proteins. Genome Biology, 6(1), 204.

    Article  PubMed  PubMed Central  Google Scholar 

  • Di Paolo, G., Antonsson, B., Kassel, D., Riederer, B. M., & Grenningloh, G. (1997). Phosphorylation regulates the microtubule-destabilizing activity of stathmin and its interaction with tubulin. FEBS Letters, 416(2), 149–152.

    Article  PubMed  Google Scholar 

  • Ferreira, T. A., & Blackman, A. V. (2014). Neuronal morphometry directly from bitmap images. Nature Methods, 11(10), 982–984.

    Article  CAS  PubMed  Google Scholar 

  • Ferreira, S. M., Navarro, A. M., Magalhaes, P. K., & Maciel, L. M. (2014). Iodine insufficiency in pregnant women from the State of São Paulo. Arquivos Brasileiros de Endocrinologia e Metabologia, 58(3), 282–287.

    Article  PubMed  Google Scholar 

  • Gerges, N. Z., & Alkadhi, K. A. (2004). Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement. Hippocampus, 14(1), 40–45.

    Article  CAS  PubMed  Google Scholar 

  • Grenningloh, G., Soehrman, S., Bondallaz, P., Ruchti, E., & Cadas, H. (2004). Role of the microtubule destabilizing proteins SCG10 and stathmin in neuronal growth. Journal of Neurobiology, 58(1), 60–69.

    Article  CAS  PubMed  Google Scholar 

  • Griffin, G. D., & Flanagan-Cato, L. M. (2008). Estradiol and progesterone differentially regulate the dendritic arbor of neurons in the hypothalamic ventromedial nucleus of the female rat (Rattus norvegicus). Journal of Comparative Neurology, 510(6), 631–640.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gundersen, G. G., Gomes, E. R., & Wen, Y. (2004). Cortical control of microtubule stability and polarization. Current Opinion in Cell Biology, 16(1), 106–112.

    Article  CAS  PubMed  Google Scholar 

  • Haeusgen, W., Boehm, R., Zhao, Y., Herdegen, T., & Waetzig, V. (2009). Specific activities of individual c-Jun N-terminal kinases in the brain. Neuroscience, 161(4), 951–959.

    Article  CAS  PubMed  Google Scholar 

  • Jan, Y. N., & Jan, L. Y. (2003). The control of dendrite development. Neuron, 40(2), 229–242.

    Article  CAS  PubMed  Google Scholar 

  • Jarrard, L. E. (1993). On the role of the hippocampus in learning and memory in the rat. Behavioral and Neural Biology, 60(1), 9–26.

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann, W. E., & Moser, H. W. (2000). Dendritic anomalies in disorders associated with mental retardation. Cerebral Cortex, 10(10), 981–991.

    Article  CAS  PubMed  Google Scholar 

  • Kimura-Kuroda, J., Nagata, I., Negishi-Kato, M., & Kuroda, Y. (2002). Thyroid hormone-dependent development of mouse cerebellar Purkinje cells in vitro. Developmental Brain Research, 137(1), 55–65.

    Article  CAS  PubMed  Google Scholar 

  • Kuan, C. Y., Yang, D. D., Samanta Roy, D. R., Davis, R. J., Rakic, P., & Flavell, R. A. (1999). The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron, 22(4), 667–676.

    Article  CAS  PubMed  Google Scholar 

  • Lavado-Autric, R., Ausó, E., García-Velasco, J. V., Arufe Mdel, C., Escobar del Rey, F., Berbel, P., et al. (2003). Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny. Journal of Clinical Investigation, 111(7), 1073–1082.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu, H. X., Zhang, J. J., Zheng, P., & Zhang, Y. (2005). Altered expression of MAP-2, GAP-43, and synaptophysin in the hippocampus of rats with chronic cerebral hypoperfusion correlates with cognitive impairment. Molecular Brain Research, 139(1), 169–177.

    Article  CAS  PubMed  Google Scholar 

  • Melse-Boonstra, A., & Jaiswal, N. (2010). Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Practice & Research Clinical Endocrinology & Metabolism, 24(1), 29–38.

    Article  CAS  Google Scholar 

  • Miller, F. D., & Kaplan, D. R. (2003). Signaling mechanisms underlying dendrite formation. Current Opinion in Neurobiology, 13(3), 391–398.

    Article  CAS  PubMed  Google Scholar 

  • Min, H., Dong, J., Wang, Y., Wang, Y., Teng, W. P., Xi, Q., et al. (2016a). Maternal Hypothyroxinemia-induced neurodevelopmental impairments in the progeny. Molecular Neurobiology, 53, 1613–1624.

    Article  CAS  PubMed  Google Scholar 

  • Min, H., Dong, J., Wang, Y., Wang, Y., Yu, Y., Shan, Z. Y., et al. (2016b). Marginal iodine deficiency affects dendritic spine development by disturbing the function of Rac1 signaling pathway on cytoskeleton. Molecular Neurobiology. doi:10.1007/s12035-015-9657-5.

    Google Scholar 

  • Moriguchi, T., Kawachi, K., Kamakura, S., Masuyama, N., Yamanaka, H., Matsumoto, K., et al. (1999). Distinct domains of mouse dishevelled are responsible for the c-Jun N-terminal kinase/stress-activated protein kinase activation and the axis formation in vertebrates. Journal of Biological Chemistry, 274(43), 30957–30962.

    Article  CAS  PubMed  Google Scholar 

  • Ng, D. C., Zhao, T. T., Yeap, Y. Y., Ngoei, K. R., & Bogoyevitch, M. A. (2010). c-Jun N-terminal kinase phosphorylation of stathmin confers protection against cellular stress. Journal of Biological Chemistry, 285(37), 29001–29013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nogales, E. (2001). Structural insight into microtubule function. Annual Review of Biophysics and Biomolecular Structure, 30, 397–420.

    Article  CAS  PubMed  Google Scholar 

  • Nolan, M. F., Malleret, G., Dudman, J. T., Buhl, D. L., Santoro, B., Gibbs, E., et al. (2004). A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell, 119(5), 719–732.

    CAS  PubMed  Google Scholar 

  • Ogawa, T., & Hirokawa, N. (2015). Microtubule destabilizer KIF2A undergoes distinct site-specific phosphorylation cascades that differentially affect neuronal morphogenesis. Cell Reports, 12(11), 1774–1788.

    Article  CAS  PubMed  Google Scholar 

  • Ohkawa, N., Fujitani, K., Tokunaga, E., Furuya, S., & Inokuchi, K. (2007). The microtubule destabilizer stathmin mediates the development of dendritic arbors in neuronal cells. Journal of Cell Science, 120(Pt 8), 1447–1456.

    Article  CAS  PubMed  Google Scholar 

  • Oyanagi, K., Negishi, T., & Tashiro, T. (2015). Action of thyroxine on the survival and neurite maintenance of cerebellar granule neurons in culture. Journal of Neuroscience Research, 93(4), 592–603.

    Article  CAS  PubMed  Google Scholar 

  • Parrish, J. Z., Emoto, K., Kim, M. D., & Jan, Y. N. (2007). Mechanisms that regulate establishment, maintenance, and remodeling of dendritic fields. Annual Review of Neuroscience, 30, 399–423.

    Article  CAS  PubMed  Google Scholar 

  • Patel, J., Landers, K., Li, H., Mortimer, R. H., & Richard, K. (2011). Thyroid hormones and fetal neurological development. Journal of Endocrinology, 209(1), 1–8.

    Article  CAS  PubMed  Google Scholar 

  • Pearce, E. N. (2012). Effects of iodine deficiency in pregnancy. Journal of Trace Elements in Medicine and Biology, 26(2–3), 131–133.

    Article  CAS  PubMed  Google Scholar 

  • Pokorný, J., & Yamamoto, T. (1981). Postnatal ontogenesis of hippocampal CA1 area in rats. I. Development of dendritic arborisation in pyramidal neurons. Brain Research Bulletin, 7(2), 113–120.

    Article  PubMed  Google Scholar 

  • Priel, A., Tuszynski, J. A., & Woolf, N. J. (2010). Neural cytoskeleton capabilities for learning and memory. Journal of Biological Physics, 36(1), 3–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rakic, P., Knyihar-Csillik, E., & Csillik, B. (1996). Polarity of microtubule assemblies during neuronal cell migration. Proceedings of the National Academy of Sciences of the United States of America, 93(17), 9218–9222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reeves, P. G., Nielsen, F. H., & Fahey, G. C, Jr. (1993). AIN-93 purified diets for laboratory rodents: Final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet. Journal of Nutrition, 123(11), 1939–1951.

    CAS  PubMed  Google Scholar 

  • Rivas, M., & Naranjo, J. R. (2007). Thyroid hormones, learning and memory. Genes Brain Behavior, 6(Suppl 1), 40–44.

    Article  CAS  Google Scholar 

  • Sánchez, C., Diaz-Nido, J., & Avila, J. (2000). Phosphorylation of microtubule-associated protein 2 (MAP2) and its relevance for the regulation of the neuronal cytoskeleton function. Progress in Neurobiology, 61(2), 133–168.

    Article  PubMed  Google Scholar 

  • Teng, J., Takei, Y., Harada, A., Nakata, T., Chen, J., & Hirokawa, N. (2001). Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization. Journal of Cell Biology, 155(1), 65–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Urbanska, M., Blazejczyk, M., & Jaworski, J. (2008). Molecular basis of dendritic arborization. Acta Neurobiologiae Experimentalis (Wars), 68(2), 264–288.

    Google Scholar 

  • Wang, Y., Wang, Y., Dong, J., Wei, W., Song, B., Min, H., et al. (2014). Developmental hypothyroxinaemia and hypothyroidism limit dendritic growth of cerebellar Purkinje cells in rat offspring: Involvement of microtubule-associated protein 2 (MAP2) and stathmin. Neuropathology and Applied Neurobiology, 40(4), 398–415.

    Article  CAS  PubMed  Google Scholar 

  • Watutantrige Fernando, S., Cavedon, E., Nacamulli, D., Pozza, D., Ermolao, A., Zaccaria, M., et al. (2016). Iodine status from childhood to adulthood in females living in North-East Italy: Iodine deficiency is still an issue. European Journal of Nutrition, 55(1), 335–340.

    Article  CAS  PubMed  Google Scholar 

  • Wei, W., Wang, Y., Wang, Y., Dong, J., Min, H., Song, B., et al. (2013). Developmental hypothyroxinaemia induced by maternal mild iodine deficiency delays hippocampal axonal growth in the rat offspring. Journal of Neuroendocrinology, 25(9), 852–862.

    Article  CAS  PubMed  Google Scholar 

  • Weston, C. R., & Davis, R. J. (2007). The JNK signal transduction pathway. Current Opinion in Cell Biology, 19(2), 142–149.

    Article  CAS  PubMed  Google Scholar 

  • Xu, X., Lu, Y., Zhang, G., Chen, L., Tian, D., Shen, X., et al. (2014). Bisphenol A promotes dendritic morphogenesis of hippocampal neurons through estrogen receptor-mediated ERK1/2 signal pathway. Chemosphere, 96, 129–137.

    Article  CAS  PubMed  Google Scholar 

  • Yip, Y. Y., Yeap, Y. Y., Bogoyevitch, M. A., & Ng, D. C. (2014). Differences in c-Jun N-terminal kinase recognition and phosphorylation of closely related stathmin-family members. Biochemical and Biophysical Research Communications, 446(1), 248–254.

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann, M. B. (2009). Iodine deficiency. Endocrine Reviews, 30(4), 376–408.

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann, M. B., & Andersson, M. (2012). Update on iodine status worldwide. Current Opinion in Endocrinology, Diabetes, and Obesity, 19(5), 382–387.

    Article  CAS  PubMed  Google Scholar 

  • Zimmermann, M. B., Gizak, M., Abbott, K., Andersson, M., & Lazarus, J. H. (2015). Iodine deficiency in pregnant women in Europe. Lancet Diabetes & Endocrinology, 3(9), 672–674.

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant Numbers 81102126) and Important Platform of Science and Technology for the Universities in Liaoning Province (Grant Number 16010) and Program for Liaoning Innovative Research Team in University (Grant Number LT2015028).

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Authors and Affiliations

  1. Department of Occupational and Environmental Health, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, 110122, People’s Republic of China

    Hui Min, Yi Wang, Jing Dong, Yuan Wang, Ye Yu & Jie Chen

  2. Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Hospital of China Medical University, Shenyang, People’s Republic of China

    Zhongyan Shan & Weiping Teng

  3. Department of Physiology, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA

    Qi Xi

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  1. Hui Min
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  2. Yi Wang
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Min, H., Wang, Y., Dong, J. et al. Effects of Maternal Marginal Iodine Deficiency on Dendritic Morphology in the Hippocampal CA1 Pyramidal Neurons in Rat Offspring. Neuromol Med 18, 203–215 (2016). https://doi.org/10.1007/s12017-016-8391-0

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